Publications by authors named "Wallace L McKeehan"

73 Publications

Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer.

Cancer Res 2018 08 11;78(16):4459-4470. Epub 2018 Jun 11.

Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas.

The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression. FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer. http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095720PMC
August 2018

A tribute to Dr. Gordon Hisashi Sato (December 24, 1927-March 31, 2017).

In Vitro Cell Dev Biol Anim 2018 Mar 12;54(3):177-193. Epub 2018 Feb 12.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA.

Gordon H. Sato, an innovator in mammalian tissue culture and integrated cellular physiology, passed away in 2017. In tribute to Dr. Sato, In Vitro Cellular and Developmental Biology-Animal presents a collection of invited remembrances from six colleagues whose associations with Dr. Sato spanned more than 40 years. Dr. Sato was a past president of the Tissue Culture Association (now the Society for In Vitro Biology), editor-in-chief of In Vitro Cellular and Developmental Biology (1987-1991), and the recipient of the lifetime achievement award from the Society for In Vitro Biology (2002). He was elected to the US National Academy of Sciences in 1984.
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http://dx.doi.org/10.1007/s11626-018-0230-1DOI Listing
March 2018

Fibroblast growth factors, old kids on the new block.

Semin Cell Dev Biol 2016 05 6;53:155-67. Epub 2016 Jan 6.

Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030-3303, United States. Electronic address:

The fibroblast growth factors (FGFs) are a family of cell intrinsic regulatory peptides that control a broad spectrum of cellular activities. The family includes canonic FGFs that elicit their activities by activating the FGF receptor (FGFR) tyrosine kinase and non-canonic members that elicit their activities intracellularly and via FGFR-independent mechanisms. The FGF signaling axis is highly complex due to the existence of multiple isoforms of both ligands and receptors, as well as cofactors that include the chemically heterogeneous heparan sulfate (HS) cofactors, and in the case of endocrine FGFs, the Klotho coreceptors. Resident FGF signaling controls embryonic development, maintains tissue homeostasis, promotes wound healing and tissue regeneration, and regulates functions of multiple organs. However, ectopic or aberrant FGF signaling is a culprit for various diseases, including congenital birth defects, metabolic disorder, and cancer. The molecular mechanisms by which the specificity of FGF signaling is achieved remain incompletely understood. Since its application as a druggable target has been gradually recognized by pharmaceutical companies and translational researchers, understanding the determinants of FGF signaling specificity has become even more important in order to get into the position to selectively suppress a particular pathway without affecting others to minimize side effects.
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http://dx.doi.org/10.1016/j.semcdb.2015.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875805PMC
May 2016

Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed.

Aging Cell 2016 Apr 10;15(2):370-9. Epub 2016 Jan 10.

Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX, 77030, USA.

Autophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule-associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectinmRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S-mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild-type mice increases the levels of fibronectin and γ-H2 AX, a marker of DNA double-strand breakage. LC3-induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild-type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3-induced overexpression of fibronectin imposes stresses on MAP1S-deficient mice and dramatically reduces their lifespans. Therefore, MAP1S-mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.
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http://dx.doi.org/10.1111/acel.12441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783353PMC
April 2016

MAP1S Protein Regulates the Phagocytosis of Bacteria and Toll-like Receptor (TLR) Signaling.

J Biol Chem 2016 Jan 12;291(3):1243-50. Epub 2015 Nov 12.

From the Center for Infectious and Inflammatory Diseases and

Phagocytosis is a critical cellular process for innate immune defense against microbial infection. The regulation of phagocytosis process is complex and has not been well defined. An intracellular molecule might regulate cell surface-initiated phagocytosis, but the underlying molecular mechanism is poorly understood (1). In this study, we found that microtubule-associated protein 1S (MAP1S), a protein identified recently that is involved in autophagy (2), is expressed primarily in macrophages. MAP1S-deficient macrophages are impaired in the phagocytosis of bacteria. Furthermore, we demonstrate that MAP1S interacts directly with MyD88, a key adaptor of Toll-like receptors (TLRs), upon TLR activation and affects the TLR signaling pathway. Intriguingly, we also observe that, upon TLR activation, MyD88 participates in autophagy processing in a MAP1S-dependent manner by co-localizing with MAP1 light chain 3 (MAP1-LC3 or LC3). Therefore, we reveal that an intracellular autophagy-related molecule of MAP1S controls bacterial phagocytosis through TLR signaling.
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http://dx.doi.org/10.1074/jbc.M115.687376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714212PMC
January 2016

Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin.

Aging (Albany NY) 2015 Oct;7(10):839-53

Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.

Autophagy controls and executes the turnover of abnormally aggregated proteins. MAP1S interacts with the autophagy marker LC3 and positively regulates autophagy flux. HDAC4 associates with the aggregation-prone mutant huntingtin protein (mHTT) that causes Huntington's disease, and colocalizes with it in cytosolic inclusions. It was suggested HDAC4 interacts with MAP1S in a yeast two-hybrid screening. Here, we found that MAP1S interacts with HDAC4 via a HDAC4-binding domain (HBD). HDAC4 destabilizes MAP1S, suppresses autophagy flux and promotes the accumulation of mHTT aggregates. This occurs by an increase in the deacetylation of the acetylated MAP1S. Either suppression of HDAC4 with siRNA or overexpression of the MAP1S HBD leads to stabilization of MAP1S, activation of autophagy flux and clearance of mHTT aggregates. Therefore, specific interruption of the HDAC4-MAP1S interaction with short peptides or small molecules to enhance autophagy flux may relieve the toxicity of mHTT associated with Huntington's disease and improve symptoms of HD patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637209PMC
http://dx.doi.org/10.18632/aging.100818DOI Listing
October 2015

Overexpression of FGF9 in prostate epithelial cells augments reactive stroma formation and promotes prostate cancer progression.

Int J Biol Sci 2015 11;11(8):948-60. Epub 2015 Jun 11.

1. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA ; 2. Wenzhou Medical College, Wenzhou, Zhejiang, China ; 3. Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M, Health Science Center, College Station, TX, USA.

Bone metastasis is the major cause of morbidity and mortality of prostate cancer (PCa). Fibroblast growth factor 9 (FGF9) has been reported to promote PCa bone metastasis. However, the mechanism by which overexpression of FGF9 promotes PCa progression and metastasis is still unknown. Herein, we report that transgenic mice forced to express FGF9 in prostate epithelial cells (F9TG) developed high grade prostatic intraepithelial neoplasia (PIN) in an expression level- and time-dependent manner. Moreover, FGF9/TRAMP bigenic mice (F9TRAMP) grew advanced PCa earlier and had higher frequencies of metastasis than TRAMP littermates. We observed tumor microenvironmental changes including hypercellularity and hyperproliferation in the stromal compartment of F9TG and F9TRAMP mice. Expression of TGFβ1, a key signaling molecule overexpressed in reactive stroma, was increased in F9TG and F9TRAMP prostates. Both in vivo and in vitro data indicated that FGF9 promoted TGFβ1 expression via increasing cJun-mediated signaling. Moreover, in silico analyses showed that the expression level of FGF9 was positively associated with expression of TGFβ1 and its downstream signaling molecules in human prostate cancers. Collectively, our data demonstrated that overexpressing FGF9 in PCa cells augmented the formation of reactive stroma and promoted PCa initiation and progression.
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http://dx.doi.org/10.7150/ijbs.12468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495412PMC
May 2016

Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment.

J Biol Chem 2015 Jul 1;290(29):17745-52. Epub 2015 Jun 1.

From the Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, the Wenzhou Medical College, Wenzhou, 325030 Zhejiang, China, the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77807

Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, including basal, luminal, and neuroendocrine cells. Multiple methods have been used to identify P-SCs in adult prostates. These include in vivo renal capsule implantation of a single epithelial cell with urogenital mesenchymal cells, in vitro prostasphere and organoid cultures, and lineage tracing with castration-resistant Nkx3.1 expression (CARN), in conjunction with expression of cell type-specific markers. Both organoid culture and CARN tracing show the existence of P-SCs in the luminal compartment. Although prostasphere cells predominantly express basal cell-specific cytokeratin and P63, the lineage of prostasphere-forming cells in the P-SC hierarchy remains to be determined. Using lineage tracing with P63(CreERT2), we show here that the sphere-forming P-SCs are P63-expressing cells and reside in the basal compartment. Therefore we designate them as basal P-SCs (P-bSCs). P-bSCs are capable of differentiating into AR(+) and CK18(+) organoid cells, but organoid cells cannot form spheres. We also report that prostaspheres contain quiescent stem cells. Therefore, the results show that P-bSCs represent stem cells that are early in the hierarchy of overall prostate tissue stem cells. Understanding the contribution of the two types of P-SCs to prostate development and prostate cancer stem cells and how to manipulate them may open new avenues for control of prostate cancer progression and relapse.
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http://dx.doi.org/10.1074/jbc.M115.661033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505023PMC
July 2015

Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment.

J Biol Chem 2015 Jul 1;290(29):17753-61. Epub 2015 Jun 1.

From the Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, the Wenzhou Medical College, Wenzhou, 325030 Zhejiang, China, the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77807

Prostate stem cells (P-SCs) are capable of giving rise to all three lineages of prostate epithelial cells, which include basal, luminal, and neuroendocrine cells. Two types of P-SCs have been identified in both human and mouse adult prostates based on prostasphere or organoid cultures, cell lineage tracing, renal capsule implantation, and expression of luminal- and basal-specific proteins. The sphere-forming P-SCs are from the basal cell compartment that express P63, and are therefore designated as basal P-SCs (P-bSCs). Luminal P-SCs (P-lSCs) express luminal cytokeratins and Nkx3.1. Herein, we report that the type 2 FGF receptor (FGFR2) signaling axis is crucial for preserving stemness and preventing differentiation of P-bSCs. FGFR2 signaling mediated by FGFR substrate 2α (FRS2α) is indispensable for formation and maintenance of prostaspheres derived from P63(+) P-bSCs. Ablation of Fgfr2 in P63(+) cells in vitro causes the disintegration of prostaspheres. Ablation of Fgfr2 in vivo reduces the number of P63-expressing basal cells and enriches luminal cells. This suggests a basal stem cell-to-luminal cell differentiation. In addition, ablation of Fgfr2 in P63(+) cells causes defective postnatal development of the prostate. Therefore, the data indicate that FGFR2 signaling is critical for preserving stemness and preventing differentiation of P-bSCs.
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http://dx.doi.org/10.1074/jbc.M115.661066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505024PMC
July 2015

Hepatocyte FRS2α is essential for the endocrine fibroblast growth factor to limit the amplitude of bile acid production induced by prandial activity.

Curr Mol Med 2014 ;14(6):703-711

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, 2121 W. Holcombe Blvd., Houston, Texas.

In addition to being positively regulated by prandial activity, bile acid production is also negatively controlled by the endocrine fibroblast growth factor 19 (FGF19) or the mouse ortholog FGF15 from the ileum that represses hepatic cholesterol 7 α-hydroxylase (Cyp7a1) expression through activating FGF receptor four (FGFR4). However, how these two regulatory mechanisms interplay to control bile acid homeostasis in the body and the downstream pathways by which FGFR4 regulates Cyp7a1 expression are not fully understood. Here we report that hepatocyte FGFR substrate 2α (FRS2α), a scaffold protein essential for canonical FGFRs to activate the ERK and AKT pathways, was required for the regulation of bile acid production by the FGF15/19-FGFR4 signaling axis. This occurred through limiting the extent of increases in Cyp7a1 expression induced by prandial activity. Excess FGFR4 kinase activity reduced the amplitude of the increase whereas a lack of FGFR4 augmented the increase of Cyp7a1 expression in the liver. Ablation of Frs2α alleles in hepatocytes abrogated the regulation of Cyp7a1 expression by FGFR4. Together, the results demonstrate that FRS2α-mediated pathways are essential for the FGF15/FGF19-FGFR4 signaling axis to control bile acid homeostasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768716PMC
http://dx.doi.org/10.2174/1566524014666140724095112DOI Listing
April 2015

Effects of obesity on transcriptomic changes and cancer hallmarks in estrogen receptor-positive breast cancer.

J Natl Cancer Inst 2014 Jul 23;106(7). Epub 2014 Jun 23.

Affiliations of authors: University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX (GV-T, LPh, FZ, P-CC, J-HS, HHC, CG, CC, FJE, M-HL, S-CJY); Cancer Biology Graduate Program (GV-T, P-CC, J-HS, HHC, CC, M-HL), Genes and Development Graduate Program (CG, M-HL); Department of Molecular and Cellular Oncology (EF-M, GV-T, LPh, FZ, P-CC, J-HS, HHC, RZ, JC, CG, CC, FJE, M-HL), Department of Breast Medical Oncology (FJE, GNH, LPu); Department of Biostatistics (JE), Department of Bioinformatics and Computational Biology (YQ); Department of Pathology (YZ, YW, WFS); Department of Emergency Medicine (J-SC, S-CJY), and Department of Endocrine Neoplasia and Hormonal Disorders (S-CJY), The University of Texas MD Anderson Cancer Center, Houston, TX; Center for Cancer & Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX (YL, WLM); Present address: Breast Cancer Program, Yale Cancer Center, New Haven, CT (LPu).

Background: Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon.

Methods: We analyzed transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients. We generated transgenic (MMTV-TGFα;A (y) /a) and orthotopic/syngeneic (A (y) /a) obese mouse models to investigate the effect of obesity on tumorigenesis and tumor progression and to determine biological mechanisms using whole-genome transcriptome microarrays and protein analyses. We used a coculture system to examine the impact of adipocytes/adipokines on breast cancer cell proliferation. All statistical tests were two-sided.

Results: Functional transcriptomic analysis of patients revealed the association of obesity with 59 biological functional changes (P < .05) linked to cancer hallmarks. Gene enrichment analysis revealed enrichment of AKT-target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03) in patients. Our obese mouse models demonstrated activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold; P < .001; n = 6-7 mice per group). Metformin or everolimus can suppress obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001, respectively; n = 6-8 mice per group). The coculture model revealed that adipocyte-secreted adipokines (eg, TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocyte-induced cell proliferation and adipocyte-secreted adipokines in vitro.

Conclusions: Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity.
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http://dx.doi.org/10.1093/jnci/dju158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110474PMC
July 2014

Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells.

Oncol Rep 2014 Jul 20;32(1):65-70. Epub 2014 May 20.

Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.

Fibroblast growth factor receptor 2 (FGFR2) is thought to mediate an important signaling pathway between prostate epithelial cells and stromal cells for maintenance of homeostasis in normal prostate tissue. Abnormalities of FGFR2 have been shown in advanced prostate cancer or prostate cancer cell lines, and we previously demonstrated the tumor-suppressive effects of the restoration of FGFR2IIIb in prostate cancer cells. The aim of the present study was to determine whether FGFR2IIIb plays a role in the chemosensitivity of castration-resistant prostate cancer cells. A clonal line of PC-3 cells expressing FGFR2IIIb (PC-3R2IIIb) was established by transfection with an IRESneo2-expressing vector bearing FGFR2IIIb cDNA. The effects of chemotherapeutic agents (docetaxel, cisplatin, 5-fluorouracil and zoledronic acid) on cell viability and apoptosis were examined by MTT assay and western blot analysis, respectively. Expression levels of molecules that were markers of epithelial-to-mesenchymal transition and chemosensitivity-related proteins were assessed by western blot analysis. Viability of the PC-3R2IIIb cells was significantly lower than that of the control PC-3 cells transfected with the vector alone (PC-3neo), and viability was further suppressed by treatment with chemotherapeutic agents, particularly docetaxel. Induced expression of caspase-3 was evident in the PC-3R2IIIb cells and was further enhanced by treatment with docetaxel. Expression of N-cadherin, vimentin, survivin and XIAP was lower in the PC-3R2IIIb cells than that in the PC-3neo cells. In contrast, expression of p21 was higher in the PC-3R2IIIb cells than that in the control PC-3neo cells. These data indicate that restoration of FGFR2IIIb in castration-resistant prostate cancer cells may reverse some of the epithelial-to-mesenchymal cell properties characteristic of tumor cells and induce in part mesenchymal-to-epithelial transition properties. This together with enhancement of apoptotic pathways involving caspase-3 may enhance chemosensitivity particularly to docetaxel which is widely used in the treatment of castration-resistant prostate cancer.
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http://dx.doi.org/10.3892/or.2014.3200DOI Listing
July 2014

Stressed Liver and Muscle Call on Adipocytes with FGF21.

Front Endocrinol (Lausanne) 2013 Dec 18;4:194. Epub 2013 Dec 18.

IBT Proteomics and Nanotechnology Laboratory, Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center , Houston, TX , USA.

Fibroblast growth factor 21 (FGF21) is an emerging regulator of local and systemic metabolic homeostasis. Treatment with pharmacological levels of FGF21 alleviates obesity and associated metabolic diseases including diabetes. However, beyond anti-obesogenic effects, the normal roles and underlying mechanisms of FGF21 as an endocrine hormone remain unclear. A recent wave of studies has revealed that FGF21 is a stress-induced endocrine factor in liver, muscle, and other tissues that targets adipose tissue and adipocytes through the FGFR1-betaKlotho complex. Adipose tissues and adipocytes within diverse tissues respond with metabolites and adipokine signals that affect functions of body tissues systemically and cells within the local microenvironment adjacent to adipocytes. Normally this is to prevent impaired tissue-specific function and damage to diverse tissues secreting FGF21 in response to chronic stress. Therefore, diverse stressed tissues and the adipose tissue and adipocytes constitute a beneficial endocrine and paracrine communication network through FGF21. Here we attempt to unify these developments with beneficial pharmacological effects of FGF21 on obesity in respect to inter-organ stress communication and mechanisms.
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http://dx.doi.org/10.3389/fendo.2013.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866528PMC
December 2013

Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations.

Cancer Metab 2013 Nov 25;1(1):21. Epub 2013 Nov 25.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W, Holcombe Blvd,, Houston, TX 77030-3303, USA.

Background: Endocrine FGF21 and FGF19 target adipocytes and hepatocytes through betaKlotho (KLB) and FGFR tyrosine kinases effecting glucose, lipid and energy metabolism. Both factors alleviate obesity and metabolic abnormalities which are contributing factors to breast tumor progression. Genomic manipulation of hepatic FGFR4 has uncovered roles of endocrine FGF signaling in both metabolic and cellular homeostasis. Here we determined whether systemic and microenvironmental metabolic alterations caused by the FGFR4 deficiency affect tumorigenesis in breast where FGFR4 is negligible. Breast tumors were induced in the bigenic mice with ablation of FGFR4 and overexpression of TGFα that activates Her2 in the ductal and lobular epithelium surrounded by adipocytes. Mammary tumorigenesis and alterations in systemic and breast microenvironmental metabolic parameters and regulatory pathways were analyzed.

Results: Ablation of FGFR4 had no effect on cellular homeostasis and Her2 activity of normal breast tissue. However, the absence of FGFR4 reduced TGFα-driven breast tumor incidence and progression and improved host survival. Notable increases in hepatic and serum FGF21, ileal FGF15/19, adiponectin and adipsin, and decreases in systemic Fetuin A, IGF-1, IGFBP-1, RBP4 and TIMP1 were observed. The ablation affected adipogenesis and secretory function of adipocytes as well as lipogenesis, glycolysis and energy homeostasis associated with the functions of mitochondria, ER and peroxisomes in the breast and tumor foci. Treatment with a chemical inhibitor of NAMPT involved in the pathways inhibited the growth and survival of breast tumor cells and tumor-initiating cell-containing spheres. The FGFR4 ablation also caused elevation of inflammatory factors in the breast.

Conclusions: Although the primary role of FGFR4 in metabolism occurs in hepatocytes, its ablation results in a net inhibitory effect on mammary tumor progression. We suggest that the tumor-delaying effect of FGFR4 deficiency may be in large part due to elevated anti-obesogenic FGF21 that triggers tumor-suppressing signals from both peripheral and breast adipocytes. The predominant changes in metabolic pathways suggested roles of metabolic effects from both peripheral and breast adipocytes on metabolic reprogramming in breast epithelial cells that contribute to the suppression of tumor progression. These results provide new insights into the contribution of systemic and microenvironmental metabolic effects controlled by endocrine FGF signaling to breast carcinogenesis.
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http://dx.doi.org/10.1186/2049-3002-1-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178208PMC
November 2013

FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway.

Pflugers Arch 2014 May 26;466(5):1011-9. Epub 2013 Sep 26.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.
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http://dx.doi.org/10.1007/s00424-013-1364-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967003PMC
May 2014

Targeting fibroblast growth factor pathways in prostate cancer.

Clin Cancer Res 2013 Nov 19;19(21):5856-66. Epub 2013 Sep 19.

Authors' Affiliations: The University of Texas MD Anderson Cancer Center; and Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas.

Advanced prostate cancer carries a poor prognosis and novel therapies are needed. Research has focused on identifying mechanisms that promote angiogenesis and cellular proliferation during prostate cancer progression from the primary tumor to bone-the principal site of prostate cancer metastases. One candidate pathway is the fibroblast growth factor (FGF) axis. Aberrant expression of FGF ligands and FGF receptors leads to constitutive activation of multiple downstream pathways involved in prostate cancer progression including mitogen-activated protein kinase, phosphoinositide 3-kinase, and phospholipase Cγ. The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors-dovitinib and nintedanib-are currently in phase II clinical development for advanced prostate cancer. Preliminary results from these trials suggest that FGF pathway inhibition represents a promising new strategy to treat castrate-resistant disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926427PMC
November 2013

Fibroblast growth factor signaling is essential for self-renewal of dental epithelial stem cells.

J Biol Chem 2013 Oct 26;288(40):28952-61. Epub 2013 Aug 26.

From the Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas 77030-3303.

A constant supply of epithelial cells from dental epithelial stem cell (DESC) niches in the cervical loop (CL) enables mouse incisors to grow continuously throughout life. Elucidation of the cellular and molecular mechanisms underlying this unlimited growth potential is of broad interest for tooth regenerative therapies. Fibroblast growth factor (FGF) signaling is essential for the development of mouse incisors and for maintenance of the CL during prenatal development. However, how FGF signaling in DESCs controls the self-renewal and differentiation of the cells is not well understood. Herein, we report that FGF signaling is essential for self-renewal and the prevention of cell differentiation of DESCs in the CL as well as in DESC spheres. Inhibiting the FGF signaling pathway decreased proliferation and increased apoptosis of the cells in DESC spheres. Suppressing FGFR or its downstream signal transduction pathways diminished Lgr5-expressing cells in the CL and promoted cell differentiation both in DESC spheres and the CL. Furthermore, disruption of the FGF pathway abrogated Wnt signaling to promote Lgr5 expression in DESCs both in vitro and in vivo. This study sheds new light on understanding the mechanism by which the homeostasis, expansion, and differentiation of DESCs are regulated.
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http://dx.doi.org/10.1074/jbc.M113.506873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789993PMC
October 2013

Self-renewal and multilineage differentiation of mouse dental epithelial stem cells.

Stem Cell Res 2013 Nov 1;11(3):990-1002. Epub 2013 Jul 1.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030-3303, USA; Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M University, Houston, TX 77030-3303, USA. Electronic address:

Understanding the cellular and molecular mechanisms underlying the self-renewal and differentiation of dental epithelial stem cells (DESCs) that support the unlimited growth potential of mouse incisors is critical for developing novel tooth regenerative therapies and unraveling the pathogenesis of odontogenic tumors. However, analysis of DESC properties and regulation has been limited by the lack of an in vitro assay system and well-documented DESC markers. Here, we describe an in vitro sphere culture system to isolate the DESCs from postnatal mouse incisor cervical loops (CLs) where the DESCs are thought to reside. The dissociated cells from CLs were able to expand and form spheres for multiple generations in the culture system. Lineage tracing indicated that DESC within the spheres were epithelial in origin as evident by lineage tracing. Upon stimulation, the sphere cells differentiated into cytokeratin 14- and amelogenin-expressing and mineral material-producing cells. Compared to the CL tissue, sphere cells expressed high levels of expression of Sca-1, CD49f (also designated as integrin α6), and CD44. Fluorescence-activated cell sorting (FACS) analyses of mouse incisor CL cells further showed that the CD49f(Bright) population was enriched in sphere-forming cells. In addition, the CD49f(Bright) population includes both slow-cycling and Lgr5(+) DESCs. The in vitro sphere culture system and identification of CD49f(Bright) as a DESC marker provide a novel platform for enriching DESCs, interrogating how maintenance, cell fate determination, and differentiation of DESCs are regulated, and developing tooth regenerative therapies.
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http://dx.doi.org/10.1016/j.scr.2013.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952636PMC
November 2013

Type 1 fibroblast growth factor receptor in cranial neural crest cell-derived mesenchyme is required for palatogenesis.

J Biol Chem 2013 Jul 10;288(30):22174-83. Epub 2013 Jun 10.

College of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang 325000, China.

Cleft palate is a common congenital birth defect. The fibroblast growth factor (FGF) family has been shown to be important for palatogenesis, which elicits the regulatory functions by activating the FGF receptor tyrosine kinase. Mutations in Fgf or Fgfr are associated with cleft palate. To date, most mechanistic studies on FGF signaling in palate development have focused on FGFR2 in the epithelium. Although Fgfr1 is expressed in the cranial neural crest (CNC)-derived palate mesenchyme and Fgfr1 mutations are associated with palate defects, how FGFR1 in palate mesenchyme regulates palatogenesis is not well understood. Here, we reported that by using Wnt1(Cre) to delete Fgfr1 in neural crest cells led to cleft palate, cleft lip, and other severe craniofacial defects. Detailed analyses revealed that loss-of-function mutations in Fgfr1 did not abrogate patterning of CNC cells in palate shelves. However, it upset cell signaling in the frontofacial areas, delayed cell proliferation in both epithelial and mesenchymal compartments, prevented palate shelf elevation, and compromised palate shelf fusion. This is the first report revealing how FGF signaling in CNC cells regulates palatogenesis.
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http://dx.doi.org/10.1074/jbc.M113.463620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724669PMC
July 2013

Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress.

BMC Gastroenterol 2013 Apr 17;13:67. Epub 2013 Apr 17.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W, Holcombe Blvd,, Houston, TX 77030-3303, USA.

Background: FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.

Methods: In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.

Results: We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.

Conclusion: FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.
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http://dx.doi.org/10.1186/1471-230X-13-67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637159PMC
April 2013

Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress.

Nutr Metab (Lond) 2012 Oct 30;9(1):94. Epub 2012 Oct 30.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W, Holcombe Blvd, Houston, TX, 77030-3303, USA.

Unlabelled:

Background: Endocrine FGF19 and FGF21 exert their effects on metabolic homeostasis through fibroblast growth factor receptor (FGFR) and co-factor betaKlotho (KLB). Ileal FGF19 regulates bile acid metabolism through specifically FGFR4-KLB in hepatocytes where FGFR1 is not significant. Both FGF19 and FGF21 activate FGFR1-KLB whose function predominates in adipocytes. Recent studies using administration of FGF19 and FGF21 and genetic ablation of KLB or adipocyte FGFR1 indicate that FGFR1-KLB mediates the response of adipocytes to both FGF21 and FGF19. Here we show that adipose FGFR1 regulates lipid metabolism through direct effect on adipose tissue and indirect effects on liver under starvation conditions that cause hepatic stress.

Methods: We employed adipocyte-specific ablations of FGFR1 and FGFR2 genes in mice, and analyzed metabolic consequences in adipose tissue, liver and systemic parameters under normal, fasting and starvation conditions.

Results: Under normal conditions, the ablation of adipose FGFR1 had little effect on adipocytes, but caused shifts in expression of hepatic genes involved in lipid metabolism. Starvation conditions precipitated a concurrent elevation of serum triglycerides and non-esterified fatty acids, and increased hepatic steatosis and adipose lipolysis in the FGFR1-deficient mice. Little effect on glucose or ketone bodies due to the FGFR1 deficiency was observed.

Conclusions: Our results suggest an adipocyte-hepatocyte communication network mediated by adipocyte FGFR1 that concurrently dampens hepatic lipogenesis and adipocyte lipolysis. We propose that this serves overall to mete out and extend lipid reserves for neural fuels (glucose and ketone bodies), while at the same time governing extent of hepatosteatosis during metabolic extremes and other conditions causing hepatic stress.
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http://dx.doi.org/10.1186/1743-7075-9-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545967PMC
October 2012

Structural basis of heparan sulfate-specific degradation by heparinase III.

Protein Cell 2012 Dec 21;3(12):950-61. Epub 2012 Jul 21.

Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.

Heparinase III (HepIII) is a 73-kDa polysaccharide lyase (PL) that degrades the heparan sulfate (HS) polysaccharides at sulfate-rare regions, which are important co-factors for a vast array of functional distinct proteins including the well-characterized antithrombin and the FGF/FGFR signal transduction system. It functions in cleaving metazoan heparan sulfate (HS) and providing carbon, nitrogen and sulfate sources for host microorganisms. It has long been used to deduce the structure of HS and heparin motifs; however, the structure of its own is unknown. Here we report the crystal structure of the HepIII from Bacteroides thetaiotaomicron at a resolution of 1.6 Å. The overall architecture of HepIII belongs to the (α/α)₅ toroid subclass with an N-terminal toroid-like domain and a C-terminal β-sandwich domain. Analysis of this high-resolution structure allows us to identify a potential HS substrate binding site in a tunnel between the two domains. A tetrasaccharide substrate bound model suggests an elimination mechanism in the HS degradation. Asn260 and His464 neutralize the carboxylic group, whereas Tyr314 serves both as a general base in C-5 proton abstraction, and a general acid in a proton donation to reconstitute the terminal hydroxyl group, respectively. The structure of HepIII and the proposed reaction model provide a molecular basis for its potential practical utilization and the mechanism of its eliminative degradation for HS polysaccarides.
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http://dx.doi.org/10.1007/s13238-012-2056-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875378PMC
December 2012

A tribute to Richard G. Ham (1932-2011).

In Vitro Cell Dev Biol Anim 2012 May 12;48(5):259-70. Epub 2012 May 12.

Center for Cancer & Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.

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http://dx.doi.org/10.1007/s11626-012-9509-9DOI Listing
May 2012

Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB.

PLoS One 2012 19;7(3):e33870. Epub 2012 Mar 19.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America.

Background: Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear.

Methodology/principal Findings: We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1.

Conclusions: Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB predominantly resides. However, both FGF21 and FGF19 have the potential to activate responses of primarily the adipose tissue where FGFR1-KLB resides.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033870PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307775PMC
July 2012

The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy.

Autophagy 2012 Apr 1;8(4):690-1. Epub 2012 Apr 1.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.

The fibroblast growth factor (FGF) signaling axis plays important roles in heart development. Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Using genetically engineered mouse and in vitro cultured embryoid body (EB) models, we demonstrate that FGF signaling suppresses premature differentiation of heart progenitor cells, as well as autophagy in outflow tract (OFT) myocardiac cells. The FGF also promotes mesoderm differentiation in embryonic stem cells (ESCs) but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, inhibition of FGF signaling increases myocardial differentiation and autophagy in both ex vivo cultured embryos and EBs, whereas activation of autophagy promotes myocardial differentiation. Thus, a link between FGF signals preventing premature differentiation of heart progenitor cells and suppression of autophagy has been established. These findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, and suggest a new venue to regulate stem/progenitor cell differentiation.
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http://dx.doi.org/10.4161/auto.19290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405844PMC
April 2012

MAP1S enhances autophagy to suppress tumorigenesis.

Autophagy 2012 Feb 1;8(2):278-80. Epub 2012 Feb 1.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.

Microtubule-associated protein 1 small form (MAP1S; originally named C19ORF5) was identified as serving as linkers to connect mitochondria with microtubules for trafficking, and to bridge the autophagy machinery with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. We found that MAP1S levels become elevated immediately in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Elevation of MAP1S enhances autophagy to remove p62-associated aggresomes and dysfunctional organelles that trigger DNA double-strand (DSB) breaks and genome instability. The early accumulation of an unstable genome prior to signs of tumorigenesis suggested that genome instability causes tumorigenesis. After tumorigenesis, tumor development then triggers the activation of autophagy to reduce genome instability in tumor foci. We concluded that an increase in MAP1S levels triggers autophagy in order to suppress genome instability so that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Thus, a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis has been established.
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http://dx.doi.org/10.4161/auto.8.2.18939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336082PMC
February 2012

Mechanism of fibrotic cardiomyopathy in mice expressing truncated Rho-associated coiled-coil protein kinase 1.

FASEB J 2012 May 25;26(5):2105-16. Epub 2012 Jan 25.

Texas A&M Health Science Center, Institute of Biosciences and Technology, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.

We have previously found that in failing human hearts, Rho-associated coiled-coil protein kinase 1 (ROCK1) is processed by caspase-3 into an active isoform, ROCKΔ1. The purpose of the current investigation was to elucidate the pathological consequences of truncated ROCK1 accumulation in the heart, the associated molecular mechanism of ROCKΔ1-mediated cardiac phenotype, and the molecular signaling between Rho kinase activation in cardiomyocytes and extracellular matrix response. We generated transgenic mice expressing ROCKΔ1 in cardiomyocytes to mimic the situation observed in human heart disease, whereas an additional kinase-deficient mouse was generated as a control. The ROCKΔ1 transgenic mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic hearts displayed activated TGFβ1 and NF-κB signaling and a release of a subset of cytokines and were susceptible to angiotensin II stress. Treatment with a Rho kinase inhibitor attenuated the fibrotic phenotype. Cardiac fibroblasts differentiated into myofibroblasts when cocultured with transgenic cardiomyocytes but not with wild-type cardiomyocytes. Inhibitors of Rho kinase as well as TGFβR1 and NF-κB decreased these effects. The serum response factor-dependent TGFβ1 regulation was shown to be responsible for the Rho kinase-mediated activation of TGFβ1 signaling. We conclude that ROCKΔ1 is a novel fibrotic factor. Activation of TGFβ1 and NF-κB signaling contributes to the Rho kinase-mediated pathological fibrosis.
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http://dx.doi.org/10.1096/fj.11-201319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336781PMC
May 2012

FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity.

Circ Res 2012 Feb 29;110(4):e29-39. Epub 2011 Dec 29.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030-3303, USA.

Rationale: Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood.

Objective: To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation.

Methods And Results: Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2α (Frs2α) in heart progenitor cells, we demonstrate that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body cultures of mouse embryonic stem cells, we reveal that FGF signaling promotes mesoderm differentiation in embryonic stem cells but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2α-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa.

Conclusions: The results indicate that the FGF/FRS2α-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy. The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.255950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677753PMC
February 2012

Autophagy enhanced by microtubule- and mitochondrion-associated MAP1S suppresses genome instability and hepatocarcinogenesis.

Cancer Res 2011 Dec 28;71(24):7537-46. Epub 2011 Oct 28.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA.

Dysfunctional autophagy is associated with tumorigenesis; however, the relationship between the two processes remains unclear. In the present study, we showed that MAP1S levels immediately become elevated in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Upregulation of MAP1S enhanced autophagy to remove aggresomes and dysfunctional organelles that trigger DNA double-strand breaks and genome instability. The early accumulation of an unstable genome before signs of tumorigenesis indicated that genome instability caused tumorigenesis. After tumorigenesis, tumor development triggered the activation of autophagy to reduce genome instability in tumor foci. We, therefore, conclude that an increase in MAP1S levels triggers autophagy to suppress genome instability such that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Taken together, the data establish a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-2170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242898PMC
December 2011

FRS2α is essential for the fibroblast growth factor to regulate the mTOR pathway and autophagy in mouse embryonic fibroblasts.

Int J Biol Sci 2011 15;7(8):1114-21. Epub 2011 Sep 15.

Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030-3303, USA.

Although the fibroblast growth factor (FGF) signaling axis plays important roles in cell survival, proliferation, and differentiation, the molecular mechanism underlying how the FGF elicits these diverse regulatory signals is not well understood. By using the Frs2α null mouse embryonic fibroblast (MEF) in conjunction with inhibitors to multiple signaling pathways, here we report that the FGF signaling axis activates mTOR via the FGF receptor substrate 2α (FRS2α)-mediated PI3K/Akt pathway, and suppresses autophagy activity in MEFs. In addition, the PI3K/Akt pathway regulated mTOR is crucial for the FGF signaling axis to suppress autophagy in MEFs. Since autophagy has been proposed to play important roles in cell survival, proliferation, and differentiation, the findings suggest a novel mechanism for the FGF signaling axis to transmit regulatory signals to downstream effectors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174388PMC
http://dx.doi.org/10.7150/ijbs.7.1114DOI Listing
January 2012