Publications by authors named "Ramon Parsons"

82 Publications

AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild-type KRAS and BRAF by destabilizing Aurora kinase B.

Cancer Discov 2021 Jul 23. Epub 2021 Jul 23.

Oncological Sciences, Icahn School of Medicine at Mount Sinai

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K/PTEN pathway lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation but not kinase inhibition profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2/M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader resistant lines were associated with low AKT phosphorylation, wild type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K/PTEN pathway mutation without RAS pathway mutation, suggesting that these cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0815DOI Listing
July 2021

NOTCH and EZH2 collaborate to repress PTEN expression in breast cancer.

Commun Biol 2021 03 9;4(1):312. Epub 2021 Mar 9.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Downregulation of the PTEN tumor suppressor transcript is frequent in breast cancer and associates with poor prognosis and triple-negative breast cancer (TNBC) when comparing breast cancers to one another. Here we show that in almost all cases, when comparing breast tumors to adjacent normal ducts, PTEN expression is decreased and the PRC2-associated methyltransferase EZH2 is increased. We further find that when comparing breast cancer cases in large cohorts, EZH2 inversely correlates with PTEN expression. Within the highest EZH2 expressing group, NOTCH alterations are frequent, and also associate with decreased PTEN expression. We show that repression of PTEN occurs through the combined action of NOTCH (NOTCH1 or NOTCH2) and EZH2 alterations in a subset of breast cancers. In fact, in cases harboring NOTCH1 mutation or a NOTCH2 fusion gene, NOTCH drives EZH2, HES-1, and HEY-1 expression to repress PTEN transcription at the promoter, which may contribute to poor prognosis in this subgroup. Restoration of PTEN expression can be achieved with an EZH2 inhibitor (UNC1999), a γ-secretase inhibitor (Compound E), or knockdown of EZH2 or NOTCH. These findings elucidate a mechanism of transcriptional repression of PTEN induced by NOTCH1 or NOTCH2 alterations, and identifies actionable signaling pathways responsible for driving a large subset of poor-prognosis breast cancers.
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http://dx.doi.org/10.1038/s42003-021-01825-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943788PMC
March 2021

Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of Expanded Human Hematopoietic Stem Cells.

Front Cell Dev Biol 2020 15;8:592348. Epub 2020 Dec 15.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to cultures expands the number of phenotypically identifiable HSCs, it frequently alters the transcriptomic and metabolic profiles, therefore, compromising their long-term (LT) hematopoietic reconstitution capacity. Within the heterogeneous pool of expanded HSCs, the precise phenotypic, transcriptomic and metabolic profile and thus, the identity of HSCs that confer LT repopulation potential remains poorly described. Utilizing valproic acid (VPA) in cultures of umbilical cord blood (UCB)-CD34 cells, we demonstrate that expanded HSCs phenotypically marked by expression of the stem cell markers CD34, CD90 and EPCR (CD201) are highly enriched for LT-HSCs. Furthermore, we report that low mitochondrial membrane potential, and, hence, mitochondrial activity distinguishes LT-HSCs within the expanded pool of phenotypically defined HSCs. Remarkably, such reduced mitochondrial activity is restricted to cells with the highest expression levels of CD34, CD90 and EPCR phenotypic markers. Together, our findings reveal that high expression of CD34, CD90 and EPCR in conjunction with low mitochondrial activity is critical for identification of functional LT-HSCs generated within expansion cultures.
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http://dx.doi.org/10.3389/fcell.2020.592348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769876PMC
December 2020

Cooperation Between Distinct Cancer Driver Genes Underlies Intertumor Heterogeneity in Hepatocellular Carcinoma.

Gastroenterology 2020 12 16;159(6):2203-2220.e14. Epub 2020 Aug 16.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background And Aims: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity.

Methods: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo.

Results: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes.

Conclusions: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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http://dx.doi.org/10.1053/j.gastro.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726023PMC
December 2020

Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer.

Prostate Cancer Prostatic Dis 2020 12 13;23(4):718-723. Epub 2020 Jul 13.

Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Background: The loss of PTEN function presents in up to 50% of late-stage prostate cancers, and is therefore a potential target for therapeutics. PTEN-deficient cells depend on de novo pyrimidine synthesis, a feature that can present a vulnerability.

Methods: We utilized in vitro growth assays and in vivo xenograft models to test the effect of de novo pyrimidine synthesis inhibition on prostate cell lines.

Results: Here, we demonstrate that PTEN-deficient prostate cancer cell lines are susceptible to inhibition of de novo pyrimidine synthesis by leflunomide. Tumor growth inhibition was observed in vitro and in vivo following leflunomide treatment, and is likely due to an overwhelming accumulation of DNA damage.

Conclusions: Our work highlights that synthetic lethality arises upon the combination of PTEN loss and leflunomide treatment in prostate cancer, and may present a therapeutic opportunity for this patient population.
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http://dx.doi.org/10.1038/s41391-020-0251-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666085PMC
December 2020

and Mutations Promote 4NQO-Initated Head and Neck Tumor Progression and Metastasis in Mice.

Mol Cancer Res 2020 06 9;18(6):822-834. Epub 2020 Mar 9.

Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

The PI3K signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the gene. Here, we present novel genetically engineered mouse models (GEMM) carrying a GOF allele (E20) alone or in combination with heterozygous - (p53) mutation with tissue-specific expression to interrogate the role of oncogenic in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF mutation promoted progression of 4-nitroquinoline 1-oxide-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared with those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone and , regardless of p53 and/or p16 status. Given the prevalence of mutations in and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with mutation represents an opportunity to a subset of patients with HNSCC. IMPLICATIONS: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in patients with HNSCC with mutation.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272268PMC
June 2020

Discovery of the PTEN Tumor Suppressor and Its Connection to the PI3K and AKT Oncogenes.

Authors:
Ramon Parsons

Cold Spring Harb Perspect Med 2020 08 3;10(8). Epub 2020 Aug 3.

Department of Oncological Sciences, Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

PTEN (phosphatase and tensin homolog on chromosome 10) was discovered over 20 years ago in 1997 and linked to the phosphatidylinositol 3-kinase (PI3K) and AKT oncogenes the following year. The discovery of PTEN emerged from the linked concepts of oncogenes and tumor suppressor genes that cause and prevent cancer and the fields of tumor viruses and human cancer genetics from which these two concepts arose. While much has been learned since, the initial discovery and characterization, including the discovery that PTEN is a regulator of PI3K and AKT, provide the foundation on which we continue to build our knowledge. To provide the context in which these cancer genes were discovered, background information that led to their discovery will also be discussed, which will hopefully be a useful guide for readers seeking to build on the work of others.
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http://dx.doi.org/10.1101/cshperspect.a036129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397838PMC
August 2020

Discovery of a first-in-class EZH2 selective degrader.

Nat Chem Biol 2020 02 9;16(2):214-222. Epub 2019 Dec 9.

Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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http://dx.doi.org/10.1038/s41589-019-0421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609PMC
February 2020

PTEN interacts with the transcription machinery on chromatin and regulates RNA polymerase II-mediated transcription.

Nucleic Acids Res 2019 06;47(11):5573-5586

Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1470 Author afMadison Avenue, New York, NY 10029, USA.

Regulation of RNA polymerase II (RNAPII)-mediated transcription controls cellular phenotypes such as cancer. Phosphatase and tensin homologue deleted on chromosome ten (PTEN), one of the most commonly altered tumor suppressors in cancer, affects transcription via its role in antagonizing the PI3K/AKT signaling pathway. Using co-immunoprecipitations and proximal ligation assays we provide evidence that PTEN interacts with AFF4, RNAPII, CDK9, cyclin T1, XPB and CDK7. Using ChIP-seq, we show that PTEN co-localizes with RNAPII and binds to chromatin in promoter and putative enhancer regions identified by histone modifications. Furthermore, we show that loss of PTEN affects RNAPII occupancy in gene bodies and further correlates with gene expression changes. Interestingly, PTEN binds to promoters and negatively regulates the expression of genes involved in transcription including AFF4 and POL2RA, which encodes a subunit of RNAPII. Loss of PTEN also increased cells' sensitivity to transcription inhibition via small molecules, which could provide a strategy to target PTEN-deficient cancers. Overall, our work describes a previously unappreciated role of nuclear PTEN, which by interacting with the transcription machinery in the context of chromatin exerts an additional layer of regulatory control on RNAPII-mediated transcription.
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http://dx.doi.org/10.1093/nar/gkz272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582409PMC
June 2019

Restoring tumor suppression.

Authors:
Ramon Parsons

Science 2019 05;364(6441):633-634

The Tisch Cancer Institute at Mount Sinai, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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http://dx.doi.org/10.1126/science.aax5526DOI Listing
May 2019

Mouse ER+/PIK3CA breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents.

Oncogene 2019 01 3;38(1):47-59. Epub 2018 Aug 3.

Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.
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http://dx.doi.org/10.1038/s41388-018-0436-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596308PMC
January 2019

Ten Essential Practices for Developing or Reforming a Biostatistics Core for a NCI Designated Cancer Center.

JNCI Cancer Spectr 2018 Jan 28;2(1):pky010. Epub 2018 Apr 28.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.

There are 69 National Cancer Institute (NCI) designated Cancer Centers (CCs) in the United States. Biostatistical collaboration is pivotal in cancer research, and support for a cancer biostatistics shared resource facility (C-BSRF) is included in the award. Although the services and staff needed in a C-BSRF have been outlined in general terms and best practices for biostatistical consultations and collaboration in an academic health center have been agreed upon, implementing these practices in the demanding setting of cancer centers interested in pursuing or maintaining NCI designation remains challenging. We surveyed all C-BSRF websites to assess their organizational charts, governance, size, services provided, and financial models and have identified 10 essential practices for the development of a successful C-BSRF. Here, we share our success with, and barriers to, implementation of these practices. Showcasing development plans for these essential practices resulted in an NCI score of "Excellent to Outstanding" for our C-BSRF in 2015, and performance metrics in 2016-2017 demonstrated notable improvement since our original Cancer Center Support Grant (CCSG) application in 2014. We believe that the essential practices described here can be adapted and adjusted, as needed, for CCs of various sizes and with different types of cancer research programs.
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http://dx.doi.org/10.1093/jncics/pky010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649702PMC
January 2018

Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity.

Immunity 2017 12 12;47(6):1169-1181.e7. Epub 2017 Dec 12.

Department of Pediatrics, Columbia University, New York, NY 10032, USA. Electronic address:

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl mice, which lack the NH-amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy.
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http://dx.doi.org/10.1016/j.immuni.2017.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738266PMC
December 2017

p53 Maintains Baseline Expression of Multiple Tumor Suppressor Genes.

Mol Cancer Res 2017 08 8;15(8):1051-1062. Epub 2017 May 8.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including , and through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer. In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587155PMC
August 2017

Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications.

Transl Oncol 2017 Jun 24;10(3):357-366. Epub 2017 Mar 24.

Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574. Electronic address:

Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.
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http://dx.doi.org/10.1016/j.tranon.2017.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369368PMC
June 2017

PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.

Cancer Discov 2017 04 2;7(4):380-390. Epub 2017 Mar 2.

Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of -mutant cells was dependent on glutamine flux through the pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase -mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in -deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with -mutant cancers. We have found a prospective targeted therapy for -deficient tumors, with efficacy and in tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation of .
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http://dx.doi.org/10.1158/2159-8290.CD-16-0612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562025PMC
April 2017

Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer.

BMC Cancer 2016 08 2;16:587. Epub 2016 Aug 2.

Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden.

Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.

Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively.

Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression.

Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.
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http://dx.doi.org/10.1186/s12885-016-2609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971667PMC
August 2016

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs).

J Biol Chem 2016 09 1;291(38):20042-54. Epub 2016 Aug 1.

From the Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029 and

Downstream of receptor tyrosine kinase and G protein-coupled receptor (GPCR) stimulation, the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchange factor (PREX) family of guanine nucleotide exchange factors (GEFs) activates Rho GTPases, leading to important roles for PREX proteins in numerous cellular processes and diseases, including cancer. PREX1 and PREX2 GEF activity is activated by the second messengers PIP3 and Gβγ, and further regulation of PREX GEF activity occurs by phosphorylation. Stimulation of receptor tyrosine kinases by neuregulin and insulin-like growth factor 1 (IGF1) leads to the phosphorylation of PREX1; however, the kinases that phosphorylate PREX1 downstream of these ligands are not known. We recently reported that the p21-activated kinases (PAKs), which are activated by GTP-bound Ras-related C3 botulinum toxin substrate 1 (Rac1), mediate the phosphorylation of PREX2 after insulin receptor activation. Here we show that certain phosphorylation events on PREX1 after insulin, neuregulin, and IGF1 treatment are PAK-dependent and lead to a reduction in PREX1 binding to PIP3 Like PREX2, PAK-mediated phosphorylation also negatively regulates PREX1 GEF activity. Furthermore, the onset of PREX1 phosphorylation was delayed compared with the phosphorylation of AKT, supporting a model of negative feedback downstream of PREX1 activation. We also found that the phosphorylation of PREX1 after isoproterenol and prostaglandin E2-mediated GPCR activation is partially PAK-dependent and likely also involves protein kinase A, which is known to reduce PREX1 function. Our data point to multiple mechanisms of PREX1 negative regulation by PAKs within receptor tyrosine kinase and GPCR-stimulated signaling pathways that have important roles in diseases such as diabetes and cancer.
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http://dx.doi.org/10.1074/jbc.M116.723882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025690PMC
September 2016

Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis.

Cell Rep 2016 07 23;16(2):472-486. Epub 2016 Jun 23.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.
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http://dx.doi.org/10.1016/j.celrep.2016.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972459PMC
July 2016

Molecular Pathways: Targeting the PI3K Pathway in Cancer-BET Inhibitors to the Rescue.

Clin Cancer Res 2016 06;22(11):2605-10

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

The PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases, including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extraterminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT, and ER pathways, suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance the clinical efficacy of PI3K inhibitors. Clin Cancer Res; 22(11); 2605-10. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896088PMC
June 2016

p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase.

J Biol Chem 2015 Nov 5;290(48):28915-31. Epub 2015 Oct 5.

From the Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029,

Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 2 (PREX2) is a guanine nucleotide exchange factor (GEF) for the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase, facilitating the exchange of GDP for GTP on Rac1. GTP-bound Rac1 then activates its downstream effectors, including p21-activated kinases (PAKs). PREX2 and Rac1 are frequently mutated in cancer and have key roles within the insulin-signaling pathway. Rac1 can be inactivated by multiple mechanisms; however, negative regulation by insulin is not well understood. Here, we show that in response to being activated after insulin stimulation, Rac1 initiates its own inactivation by decreasing PREX2 GEF activity. Following PREX2-mediated activation of Rac1 by the second messengers PIP3 or Gβγ, we found that PREX2 was phosphorylated through a PAK-dependent mechanism. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. Cell fractionation experiments also revealed that phosphorylation prevented PREX2 from localizing to the cellular membrane. Furthermore, the onset of insulin-induced phosphorylation of PREX2 was delayed compared with AKT. Altogether, we propose that second messengers activate the Rac1 signal, which sets in motion a cascade whereby PAKs phosphorylate and negatively regulate PREX2 to decrease Rac1 activation. This type of regulation would allow for transient activation of the PREX2-Rac1 signal and may be relevant in multiple physiological processes, including diseases such as diabetes and cancer when insulin signaling is chronically activated.
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http://dx.doi.org/10.1074/jbc.M115.668244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661405PMC
November 2015

PTEN and NEDD4 in Human Breast Carcinoma.

Pathol Oncol Res 2016 Jan 15;22(1):41-7. Epub 2015 Aug 15.

Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.

PTEN is an important tumor suppressor gene that antagonizes the oncogenic PI3K/AKT signaling pathway and has functions in the nucleus for maintaining genome integrity. Although PTEN inactivation by mutation is infrequent in breast cancer, transcript and protein levels are deficient in >25 % of cases. The E3 ubiquitin ligase NEDD4 (also known as NEDD4-1) has been reported to negatively regulate PTEN protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder, but its effect on PTEN in the breast has not been studied extensively. To investigate whether NEDD4 contributes to low PTEN levels in human breast cancer, we analyzed the expression of these proteins by immunohistochemistry across a large Swedish cohort of breast tumor specimens, and their transcript expression levels by microarrays. For both NEDD4 and PTEN, their transcript expression was significantly correlated to their protein expression. However, comparing NEDD4 expression to PTEN expression, either no association or a positive correlation was observed at the protein and transcript levels. This unexpected observation was further corroborated in two independent breast cancer cohorts from The Netherlands Cancer Institute and The Cancer Genome Atlas. Our results suggest that NEDD4 is not responsible for the frequent down-regulation of the PTEN protein in human breast carcinoma.
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http://dx.doi.org/10.1007/s12253-015-9971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681749PMC
January 2016

Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells.

Diabetes 2015 Nov 9;64(11):3784-97. Epub 2015 Jul 9.

Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL-prolactin receptor (hPRLR)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5)-cyclin-cdk signaling cascade in human β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1-3 and cdk4, as well as their nuclear translocation, all of which are associated with β-cell cycle entry. Collectively, the findings show that human β-cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments.
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http://dx.doi.org/10.2337/db15-0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613973PMC
November 2015

Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.

Cancer Cell 2015 Jun;27(6):837-51

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA. Electronic address:

Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy.
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http://dx.doi.org/10.1016/j.ccell.2015.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918409PMC
June 2015

PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion.

Sci Signal 2015 Mar 31;8(370):ra32. Epub 2015 Mar 31.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.

The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT. PREX2, a widely distributed GEF that activates the GTPase RAC1, binds to and inhibits PTEN. We used mouse embryonic fibroblasts and breast cancer cell lines to show that PTEN suppresses cell migration and invasion by blocking PREX2 activity. In addition to metabolizing the phosphoinositide PIP₃, PTEN inhibited PREX2-induced invasion by a mechanism that required the tail domain of PTEN, but not its lipid phosphatase activity. Fluorescent nucleotide exchange assays revealed that PTEN inhibited the GEF activity of PREX2 toward RAC1. PREX2 is a frequently mutated GEF in cancer, and examination of human tumor data showed that PREX2 mutation was associated with high PTEN expression. Therefore, we tested whether cancer-derived somatic PREX2 mutants, which accelerate tumor formation of immortalized melanocytes, were inhibited by PTEN. The three stably expressed, somatic PREX2 cancer mutants that we tested were resistant to PTEN-mediated inhibition of invasion but retained the ability to inhibit the lipid phosphatase activity of PTEN. In vitro analysis showed that PTEN did not block the GEF activity of two PREX2 cancer mutants and had a reduced binding affinity for the third. Thus, PTEN antagonized migration and invasion by restraining PREX2 GEF activity, and PREX2 mutants are likely selected in cancer to escape PTEN-mediated inhibition of invasion.
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http://dx.doi.org/10.1126/scisignal.2005840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874664PMC
March 2015

Analysis of intracellular PTEN signaling and secretion.

Methods 2015 May 15;77-78:164-71. Epub 2014 Nov 15.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA. Electronic address:

The tumor suppressor PTEN dephosphorylates PIP3 to inhibit PI3K signaling in cells. Altering PTEN intracellular signaling can therefore significantly affect cell behavior. Two novel mechanisms of PTEN regulation including the secretion and entry of the translational variant PTEN-L, and enzymatic inhibition by the interacting protein P-REX2, have been shown to modulate PI3K signaling, cellular proliferation and survival, and glucose metabolism. Here, we review the methods used to identify and validate the existence of both PTEN-L and the P-REX2-PTEN complex, to determine their effects on PTEN phosphatase activity, and to examine their role in cellular physiology.
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http://dx.doi.org/10.1016/j.ymeth.2014.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861994PMC
May 2015

Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy.

Clin Cancer Res 2014 Nov;20(21):5379-83

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Phosphatase and Tensin homolog deleted on chromosome Ten (PTEN) acts as a tumor suppressor through both PI3K-dependent and -independent mechanisms. Reduced PTEN activity has been shown to affect not only tumor cell proliferation and survival but also the microenvironmental context in which nascent tumors develop. As a result of the multifaceted tumor-suppressive roles of PTEN, tumors evolve by selecting for clones in which PTEN activity is lost. PTEN activity within tumors can be modulated in numerous ways, including direct mutation, epigenetic regulation, and amplification or mutation of other proteins that can regulate or degrade PTEN. These events functionally prevent PTEN protein from acting within tumor cells. Paracrine roles for PTEN gene products (exosomal PTEN and PTEN-L) have recently been identified, through which PTEN gene products produced in one cell are able to enter recipient cells and contribute to PTEN functions. In preclinical models purified PTEN-L protein was able to enter tumor xenografts and downregulate PI3K signaling as well as cause tumor cell death. Here, we review the role of PTEN as a multifaceted tumor suppressor and reflect upon the potential for PTEN restoration therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362520PMC
November 2014

Metformin and erlotinib synergize to inhibit basal breast cancer.

Oncotarget 2014 Nov;5(21):10503-17

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032. Department of Medicine, Columbia University, New York, NY 10032.

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDA-MB-468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279389PMC
http://dx.doi.org/10.18632/oncotarget.2391DOI Listing
November 2014

A unified nomenclature and amino acid numbering for human PTEN.

Sci Signal 2014 Jul 1;7(332):pe15. Epub 2014 Jul 1.

Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.
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http://dx.doi.org/10.1126/scisignal.2005560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367864PMC
July 2014

New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond.

Discoveries (Craiova) 2014 Apr-Jun;2(2):e15

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave HCSM 6-117, New York, NY 10029, USA.

The bZIP transcription factor NFIL3 (Nuclear factor Interleukin 3 regulated, also known as E4 binding protein 4, E4BP4) regulates diverse biological processes from circadian rhythm to cellular viability. Recently, a host of novel roles have been identified for NFIL3 in immunological signal transduction, cancer, aging and metabolism. Elucidating the signaling pathways that are impacted by NFIL3 and the regulatory mechanisms that it targets, inhibits or activates will be critical for developing a clearer picture of its physiological roles in disease and normal processes. This review will discuss the recent advances and emerging issues regarding NFIL3-mediated transcriptional regulation of CEBPβ and FOXO1 activated genes and signal transduction.
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http://dx.doi.org/10.15190/d.2014.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629104PMC
November 2015
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