Publications by authors named "Kristin K Deeb"

15 Publications

  • Page 1 of 1

Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.

Eur J Med Genet 2015 Oct 18;58(10):562-8. Epub 2015 Sep 18.

Center for Human Genetics, Departments of Genetics and Pediatrics, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA. Electronic address:

Cornelia de Lange syndrome (CdLS) is a rare dominantly inherited genetic multisystem developmental condition with considerable phenotypic and allelic heterogeneity. Missense and in-frame deletions within the SMC1A gene can be associated with epilepsy and milder craniofacial features. We report two females who presented with developmental delay and developed isolated medically refractory seizures with unrevealing initial laboratory, imaging and genetic evaluations. Whole exome sequencing (WES) analyses were performed and were instrumental in uncovering the genetic etiology for their conditions. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. We also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. We review previous reports of SMC1A mutations with epilepsy. SMC1A should be included in clinical gene panels for early infantile and early childhood epileptic encephalopathy.
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http://dx.doi.org/10.1016/j.ejmg.2015.09.007DOI Listing
October 2015

Routine Clinical Mutation Profiling of Non-Small Cell Lung Cancer Using Next-Generation Sequencing.

Arch Pathol Lab Med 2015 Jul;139(7):913-21

From the Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, New York. Dr Deeb is now with the University Hospitals Case Medical Center, Cleveland, Ohio; Mr Risch is now with Life Technologies, Grand Island, New York; and Dr Starostik is now with the Department of Pathology, Immunology and Laboratory Medicine, College of Medicine University of Florida, Gainesville.

Context: The availability of massive, parallel-sequencing technologies makes possible efficient, simultaneous detection of driver and druggable mutations in cancer.

Objective: To develop an amplicon-based, next-generation sequencing, mutation-detection assay for lung cancer using the 454 GS Junior (Roche Applied Science, Indianapolis, Indiana) platform.

Design: Fusion primers incorporating target sequence, 454 adaptors, and multiplex identifiers were designed to generate 35 amplicons (median length 246 base pairs) covering 8.9 kilobases of mutational hotspots in AKT1, BRAF, EGFR, ERBB2, HRAS, KRAS, NRAS, PIK3CA, and MAP2K1 genes and all exons of the PTEN gene.

Results: The assay was validated on 23 formalin-fixed, paraffin-embedded lung cancer specimens. A minimum number of reads was consistently achieved with overall median read depth of 529× per amplicon. In total, 25 point mutations and 4 insertions/deletions (indels) with a frequency of 5.5% to 93.1% mutant alleles were detected. All EGFR, ERBB2, KRAS, PIK3CA, KRAS, and PTEN mutations, as detected by next-generation sequencing, were confirmed by pyrosequencing, with the exception of 3 point mutations in a tumor sample with low mutant-allele burden (below the pyrosequencing limit of detection).

Conclusions: The GS Junior-based, targeted, resequencing assay for a focused set of non-small cell lung cancer driver genes allows for quick and sensitive detection of point mutations and indels for the most relevant therapeutic genes in this type of cancer.
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http://dx.doi.org/10.5858/arpa.2014-0095-OADOI Listing
July 2015

The c.1364C>A (p.A455E) Mutation in the CFTR Pseudogene Results in an Incorrectly Assigned Carrier Status by a Commonly Used Screening Platform.

J Mol Diagn 2015 Jul 5;17(4):360-5. Epub 2015 May 5.

Center for Human Genetics Laboratory, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address:

Cystic fibrosis (CF) is one of the most common recessive conditions among whites, with an estimated carrier frequency of 1 in 25 in the United States. Population-based CF carrier screening was implemented in the United States in 2001. The number of mutations screened by each laboratory may vary; however, the 23 most common CF mutations recommended for screening by the American College of Medical Genetics and American College of Obstetricians and Gynecologists are included in all platforms. The c.1364C>A (p.A455E) mutation located in exon 10 of the CFTR gene is one of the 23 mutations. Because CFTR exon 10 and its flanking intronic regions are duplicated and transposed onto several other chromosomes of the human genome during evolution and function as unprocessed pseudogenes, variations in the CFTR pseudogenes may confound CF screening results for mutations located in exon 10 of the CFTR gene. We report an incorrectly identified carrier status for the c.1364C>A (p.A455E) mutation in a healthy individual using the Hologic InPlex CF assay. Further analysis revealed that the mutation resides in one of the CFTR pseudogenes. Because most commercial kits and laboratory-developed tests for CF carrier screening involve a short amplicon encompassing this mutation, this finding suggests that individuals with the c.1364C>A (p.A455E) mutation may require further investigation to avoid a false assignment of CF carrier status.
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http://dx.doi.org/10.1016/j.jmoldx.2015.02.005DOI Listing
July 2015

The Value of Comprehensive Thyroid Function Testing and Family History for Early Diagnosis of MCT8 Deficiency.

Clin Pediatr (Phila) 2016 Mar 29;55(3):286-9. Epub 2015 Apr 29.

Pediatric Neurology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1177/0009922815584219DOI Listing
March 2016

Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia.

Leuk Res Rep 2014 16;3(2):86-9. Epub 2014 Oct 16.

Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.

In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations.
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http://dx.doi.org/10.1016/j.lrr.2013.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220013PMC
November 2014

Somatic mosaicism for a novel mutation in a male with severe pyruvate dehydrogenase complex deficiency.

Mol Genet Metab Rep 2014 28;1:362-367. Epub 2014 Aug 28.

Center for Human Genetics Laboratory University Hospitals Case Medical Center, Cleveland, OH, USA.

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked gene. Males with hemizygous mutations are clinically more severely affected, while those with mosaic mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of mosaicism.
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http://dx.doi.org/10.1016/j.ymgmr.2014.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121365PMC
August 2014

Multigene assays in metastatic colorectal cancer.

J Natl Compr Canc Netw 2013 Sep;11 Suppl 4:S9-17

From the aCenter for Human Genetics Laboratory, Case Western Reserve University, Cleveland, Ohio; bClinical Molecular Diagnostic Laboratory, Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California; cFulgent Therapeutics Inc, Temple City, California; and dMedical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.

Specific genomic colorectal cancer alterations are increasingly linked to prognosis and/or response to specific anticancer agents. The identification of KRAS mutations as markers of resistance to epidermal growth factor receptor (EGFR) inhibitors has paved the way to the interrogation of numerous other markers of resistance to anti-EGFR therapy, such as NRAS, BRAF, and PI3KCA mutations. Other genomic and protein expression alterations have recently been identified as potential targets of treatment or as markers of chemotherapy or targeted-therapy resistance, including ERCC1 expression, c-Met expression, PTEN expression, HER2 amplification, HER3 expression, and rare KRAS mutations. As the number of distinct validated intratumor genomic assays increases, numerous molecular assays will need to be compiled into one multigene panel assay. Several companies and academic centers are now offering multigene assays to patients with metastatic colorectal cancer and other solid tumors. This article discusses the technology behind multigene assays, its limitations, its current advantages, and its potential in the clinical care of metastatic colorectal cancer.
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http://dx.doi.org/10.6004/jnccn.2013.0221DOI Listing
September 2013

Isolation and genome-wide expression and methylation characterization of CD31+ cells from normal and malignant human prostate tissue.

Oncotarget 2013 Sep;4(9):1472-83

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.

Endothelial cells (ECs) are an important component involved in the angiogenesis. Little is known about the global gene expression and epigenetic regulation in tumor endothelial cells. The identification of gene expression and epigenetic difference between human prostate tumor-derived endothelial cells (TdECs) and those in normal tissues may uncover unique biological features of TdEC and facilitate the discovery of new anti-angiogenic targets. We established a method for isolation of CD31+ endothelial cells from malignant and normal prostate tissue obtained at prostatectomy. TdECs and normal-derived ECs (NdECs) showed >90% enrichment in primary culture and demonstrated microvascular endothelial cell characteristics such as cobblestone morphology in monolayer culture, diI-acetyl-LDL uptake and capillary-tube like formation in Matrigel®. In vitro primary cultures of ECs maintained expression of endothelial markers such as CD31, von Willebrand factor, intercellular adhesion molecule, vascular endothelial growth factor receptor 1, and vascular endothelial growth factor receptor 2. We then conducted a pilot study of transcriptome and methylome analysis of TdECs and matched NdECs from patients with prostate cancer. We observed a wide spectrum of differences in gene expression and methylation patterns in endothelial cells, between malignant and normal prostate tissues. Array-based expression and methylation data were validated by qRT-PCR and bisulfite DNA pyrosequencing. Further analysis of transcriptome and methylome data revealed a number of differentially expressed genes with loci whose methylation change is accompanied by an inverse change in gene expression. Our study demonstrates the feasibility of isolation of ECs from histologically normal prostate and prostate cancer via CD31+ selection. The data, although preliminary, indicates that there exist widespread differences in methylation and transcription between TdECs and NdECs. Interestingly, only a small proportion of perturbed gene was overlapped between American (AA) and Caucasian American (CA) patients with prostate cancer. Our study indicates that identifying gene expression and/or epigenetic differences between TdECs and NdECs may provide us with new anti-angiogenic targets. Future studies will be required to further characterize the isolated ECs and determine the biological features that can be exploited in the prognosis and therapy of prostate cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824530PMC
http://dx.doi.org/10.18632/oncotarget.1269DOI Listing
September 2013

Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription.

J Biol Chem 2011 Oct 25;286(42):36228-37. Epub 2011 Aug 25.

Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York 14214, USA.

Calcitriol, the active form of vitamin D, in combination with the glucocorticoid dexamethasone (Dex) has been shown to increase the antitumor effects of calcitriol in squamous cell carcinoma. In this study we found that pretreatment with Dex potentiates calcitriol effects by inhibiting cell growth and increasing vitamin D receptor (VDR) and VDR-mediated transcription. Treatment with actinomycin D inhibits Vdr mRNA synthesis, indicating that Dex regulates VDR expression at transcriptional level. Real time PCR shows that treatment with Dex increases Vdr transcripts in a time- and a dose-dependent manner, indicating that Dex directly regulates expression of Vdr. RU486, an inhibitor of glucocorticoids, inhibits Dex-induced Vdr expression. In addition, the silencing of glucocorticoid receptor (GR) abolishes the induction of Vdr by Dex, indicating that Dex increases Vdr transcripts in a GR-dependent manner. A fragment located 5.2 kb upstream of Vdr transcription start site containing two putative glucocorticoid response elements (GREs) was evaluated using a luciferase-based reporter assay. Treatment with 100 nm Dex induces transcription of luciferase driven by the fragment. Deletion of the GRE distal to transcription start site was sufficient to abolish Dex induction of luciferase. Also, chromatin immunoprecipitation reveals recruitment of GR to distal GRE with Dex treatment. We conclude that Dex increases VDR and vitamin D effects by increasing Vdr de novo transcription in a GR-dependent manner.
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http://dx.doi.org/10.1074/jbc.M111.244061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196110PMC
October 2011

Differential vitamin D 24-hydroxylase/CYP24A1 gene promoter methylation in endothelium from benign and malignant human prostate.

Epigenetics 2011 Aug 1;6(8):994-1000. Epub 2011 Aug 1.

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute; Buffalo, NY USA.

Epigenetic alterations occur in tumor-associated vessels in the tumor microenvironment. Methylation of the CYP24A1 gene promoter differs in endothelial cells isolated from tumors and non-tumor microenvironments in mice. The epigenetic makeup of endothelial cells of human tumor-associated vasculature is unknown due to difficulty of isolating endothelial cells populations from a heterogeneous tissue microenvironment. To ascertain CYP24A1 promoter methylation in tumor-associated endothelium, we utilized laser microdissection guided by CD31 immunohistochemistry to procure endothelial cells from human prostate tumor specimens. Prostate tissues were obtained following robotic radical prostatectomy from men with clinically localized prostate cancer. Adjacent histologically benign prostate tissues were used to compare endothelium from benign versus tumor microenvironments. Sodium bisulfite sequencing of CYP24A1 promoter region showed that the average CYP24A1 promoter methylation in the endothelium was 20% from the tumor microenvironment compared with 8.2% in the benign microenvironment (p< 0.05). A 2-fold to 17-fold increase in CYP24A1 promoter methylation was observed in the prostate tumor endothelium compared with the matched benign prostate endothelium in four patient samples, while CYP24A1 remained unchanged in two patient sample. In addition, there is no correlation of the level of CYP24A1 promoter methylation in prostate tumor-associated endothelium with that of epithelium/stroma. This study demonstrates that the CYP24A1 promoter is methylated in tumor-associated endothelium, indicating that epigenetic alterations in CYP24A1 may play a role in determining the phenotype of tumor-associated vasculature in the prostate tumor microenvironment.
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http://dx.doi.org/10.4161/epi.6.8.16536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219083PMC
August 2011

Epigenetic regulation of vitamin D 24-hydroxylase/CYP24A1 in human prostate cancer.

Cancer Res 2010 Jul 29;70(14):5953-62. Epub 2010 Jun 29.

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Calcitriol, a regulator of calcium homeostasis with antitumor properties, is degraded by the product of the CYP24A1 gene, which is downregulated in human prostate cancer by unknown mechanisms. We found that CYP24A1 expression is inversely correlated with promoter DNA methylation in prostate cancer cell lines. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) activates CYP24A1 expression in prostate cancer cells. In vitro methylation of the CYP24A1 promoter represses its promoter activity. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in prostate cancer cells. Quantitative chromatin immunoprecipitation-PCR (ChIP-qPCR) reveals that specific histone modifications are associated with the CYP24A1 promoter region. Treatment with TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with DAC and TSA increases the recruitment of vitamin D receptor to the CYP24A1 promoter. Reverse transcriptase-PCR analysis of paired human prostate samples revealed that CYP24A1 expression is downregulated in prostate malignant lesions compared with adjacent histologically benign lesions. Bisulfite pyrosequencing shows that CYP24A1 gene is hypermethylated in malignant lesions compared with matched benign lesions. Our findings indicate that repression of CYP24A1 gene expression in human prostate cancer cells is mediated in part by promoter DNA methylation and repressive histone modifications.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-0617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928678PMC
July 2010

Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy.

Cancer J 2010 Jan-Feb;16(1):1-9

Department of Medicine, The Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Considerable preclinical and epidemiologic data suggest that vitamin D may play a role in the pathogenesis, progression, and therapy for cancer. Numerous epidemiologic studies support the hypothesis that individuals with lower serum vitamin D levels have a higher risk of a number of cancers. Measures of vitamin D level in such studies include both surrogate estimates of vitamin D level (residence in more northern latitudes, history of activity, and sun exposure) as well as measured serum 25(OH) cholecalciferol levels. Perhaps, the most robust of these epidemiologic studies is that of Giovannucci et al, who developed and validated an estimate of serum 25(OH) cholecalciferol level and reported that among >40,000 individuals in the Health Professionals Study, an increase in 25(OH) cholecalciferol level of 62.5 ng/mL was associated with a reduction in the risk of head/neck, esophagus, pancreas cancers, and acute leukemia by >50%. Unfortunately, very limited data are available to indicate whether or not giving vitamin D supplements reduces the risk of cancer. Many preclinical studies indicate that exposing cancer cells, as well as vascular endothelial cells derived from tumors, to high concentrations of active metabolites of vitamin D halts progression through cell cycle, induces apoptosis and will slow or stop the growth of tumors in vivo. There are no data that one type of cancer is more or less susceptible to the effects of vitamin D. Vitamin D also potentiates the antitumor activity of a number of types of cytotoxic anticancer agents in in vivo preclinical models. Vitamin D analogues initiate signaling through a number of important pathways, but the pathway(s) essential to the antitumor activities of vitamin D are unclear. Clinical studies of vitamin D as an antitumor agent have been hampered by the lack of a suitable pharmaceutical preparation for clinical study. All commercially available formulations are inadequate because of the necessity to administer large numbers of caplets and the poor "bioavailability" of calcitriol (the most carefully studied analogue) at these high doses. Preclinical data suggest that high exposures to calcitriol are necessary for the antitumor effects. Clinical data do indicate that high doses of calcitriol (>100 mcg weekly, intravenously, and 0.15 microg /kg weekly, orally) can be given safely. The maximum tolerated dose of calcitriol is unclear. While a 250-patient trial in men with castration-resistant prostate cancer comparing docetaxel (36 mg/sqm weekly) +/- calcitriol 0.15 microg/kg indicated that calcitriol was very safe may have reduced to death rate, an adequately powered (1000 patients) randomized study of weekly docetaxel + calcitriol versus q3 week docetaxel was negative. The limitations of this trial were the unequal chemotherapy arms compared in this study and the failure to use an optimal biologic dose or maximum-tolerated dose of calcitriol. In view of the substantial preclinical and epidemiologic data supporting the potential role of vitamin D in cancer, careful studies to evaluate the impact of vitamin D replacement on the frequency of cancer and the impact of an appropriate dose and schedule of calcitriol or other active vitamin D analogue on the treatment of established cancer are indicated.
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http://dx.doi.org/10.1097/PPO.0b013e3181c51ee6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857702PMC
May 2010

Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis.

Cancer Res 2007 Sep;67(17):8065-80

Laboratory of Cell Regulation and Carcinogenesis, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.

Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based on their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simian virus 40 T/t-antigens that is associated with the biological behavior and prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair, and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb, or BRCA1 expression but not in tumors initiated through the overexpression of myc, ras, her2/neu, or polyoma middle T oncogenes. Importantly, human breast, lung, and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Because this class of epithelial tumors is generally intractable to currently existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Because these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in preclinical testing of therapies focused on these biologically important targets.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1515DOI Listing
September 2007

Vitamin D signalling pathways in cancer: potential for anticancer therapeutics.

Nat Rev Cancer 2007 Sep;7(9):684-700

Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, USA.

Epidemiological studies indicate that vitamin D insufficiency could have an aetiological role in various human cancers. Preclinical research indicates that the active metabolite of vitamin D, 1alpha,25(OH)2D3, also known as calcitriol, or vitamin D analogues might have potential as anticancer agents because their administration has antiproliferative effects, can activate apoptotic pathways and inhibit angiogenesis. In addition, 1alpha,25(OH)2D3 potentiates the anticancer effects of many cytotoxic and antiproliferative anticancer agents. Here, we outline the epidemiological, preclinical and clinical studies that support the development of 1alpha,25(OH)2D3 and vitamin D analogues as preventative and therapeutic anticancer agents.
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http://dx.doi.org/10.1038/nrc2196DOI Listing
September 2007

Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA.

J Biol Chem 2007 Mar 21;282(11):8404-13. Epub 2006 Dec 21.

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

The acetylating enzyme, spermidine/spermine N1-acetyltransferase, participates in polyamine homeostasis by regulating polyamine export and catabolism. Previously, we reported that overexpression of the enzyme in cultured tumor cells and mice activates metabolic flux through the polyamine pathway and depletes the N1-acetyltransferase coenzyme and fatty acid precursor, acetyl-CoA. Here, we investigate this possibility in spermidine/spermine N1-acetyltransferase transgenic mice in which the enzyme is systemically overexpressed and in spermidine/spermine N1-acetyltransferase knock-out mice. Tissues of the former were characterized by increased N1-acetyltransferase activity, a marked elevation in tissue and urinary acetylated polyamines, a compensatory increase in polyamine biosynthetic enzyme activity, and an increase in metabolic flux through the polyamine pathway. These polyamine effects were accompanied by a decrease in white adipose acetyl- and malonyl-CoA pools, a major (20-fold) increase in glucose and palmitate oxidation, and a distinctly lean phenotype. In SSAT-ko mice, the opposite relationship between polyamine and fat metabolism was observed. In the absence of N1-acetylation of polyamines, there was a shift in urinary and tissue polyamines indicative of a decline in metabolic flux. This was accompanied by an increase in white adipose acetyl- and malonyl-CoA pools, a decrease in adipose palmitate and glucose oxidation, and an accumulation of body fat. The latter was further exaggerated under a high fat diet, where knock-out mice gained twice as much weight as wild-type mice. A model is proposed whereby the expression status of spermidine/spermine N1-acetyltransferase alters body fat accumulation by metabolically modulating tissue acetyl- and malonyl-CoA levels, thereby influencing fatty acid biosynthesis and oxidation.
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http://dx.doi.org/10.1074/jbc.M610265200DOI Listing
March 2007