Publications by authors named "Nilotpal Roy"

23 Publications

  • Page 1 of 1

The Pdx1-Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β-Cell Function.

Diabetes 2019 09 14;68(9):1806-1818. Epub 2019 Jun 14.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN

Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β-cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β-cell activity, which included whole-animal glucose intolerance, hyperglycemia, and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β-cells lost the ability to produce the mRNAs for and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas, and we discuss how disrupting their association could influence type 1 and type 2 diabetes susceptibility.
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http://dx.doi.org/10.2337/db19-0349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702633PMC
September 2019

Epigenetics of gastrointestinal diseases: notes from a workshop.

Epigenetics 2018 30;13(4):449-457. Epub 2018 Jul 30.

a Schulze Center for Novel Therapeutics, Division of Oncology Research , Mayo Clinic , Rochester , MN , USA.

International experts gathered at the Mayo Clinic (Rochester MN, USA) on February 27th-28th, 2017 for a meeting entitled 'Basic and Translational Facets of the Epigenetics of GI Diseases'. This workshop summarized recent advances on the role of epigenetics in the pathobiology of gastrointestinal (GI) diseases. Highlights of the meeting included recent advances on the involvement of different epigenetic mechanisms in malignant and nonmalignant GI disorders and the epigenetic heterogeneity exhibited in these diseases. The translational value of epigenetic drugs, as well as the current and future use of epigenetic changes (i.e., DNA methylation patterns) as biomarkers for early detection tools or disease stratification were also important topics of discussion.
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http://dx.doi.org/10.1080/15592294.2018.1464351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140811PMC
February 2019

The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis.

J Clin Invest 2018 08 16;128(8):3475-3489. Epub 2018 Jul 16.

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
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http://dx.doi.org/10.1172/JCI94287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063489PMC
August 2018

Replication confers β cell immaturity.

Nat Commun 2018 02 2;9(1):485. Epub 2018 Feb 2.

Diabetes Center, Department of Medicine, University of California, San Francisco, CA, USA.

Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues.
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http://dx.doi.org/10.1038/s41467-018-02939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797102PMC
February 2018

Retraction for Roy et al., "DDB2, an Essential Mediator of Premature Senescence".

Mol Cell Biol 2017 06 16;37(11). Epub 2017 May 16.

Department of Biochemistry and Molecular Genetics (M/C 669), Cancer Center, University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, Illinois 60607.

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http://dx.doi.org/10.1128/MCB.00135-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440650PMC
June 2017

Atypical flat lesions derive from pancreatic acinar cells.

Pancreatology 2017 May - Jun;17(3):350-353. Epub 2017 Apr 25.

Institute of Pathology, University Clinic Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context of oncogenic stimuli.

Methods: Histological analyses were performed in a murine PDAC model that specifically expresses oncogenic Kras in adult pancreatic acinar cells. Occurrence, characterization, and lineage tracing of AFLs were investigated.

Results: Upon expression of oncogenic Kras in adult pancreatic acinar cells, AFLs with typical morphology and expression profile arise. Lineage tracing confirmed that the AFLs were of acinar origin.

Conclusions: Using a murine PDAC model, this study identifies pancreatic acinar cells as a cellular source for AFLs.
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http://dx.doi.org/10.1016/j.pan.2017.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770228PMC
March 2018

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts.

Clin Cancer Res 2017 Aug 19;23(16):4865-4874. Epub 2017 Apr 19.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.

Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid. We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712228PMC
August 2017

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.

Genes Dev 2016 12;30(24):2669-2683

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.
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http://dx.doi.org/10.1101/gad.291021.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238727PMC
December 2016

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

Nat Med 2016 05 18;22(5):497-505. Epub 2016 Apr 18.

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.
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http://dx.doi.org/10.1038/nm.4082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860133PMC
May 2016

p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia.

Cancer Res 2016 06 31;76(11):3351-63. Epub 2016 Mar 31.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas.

Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891257PMC
June 2016

Regulation of Cellular Identity in Cancer.

Dev Cell 2015 Dec;35(6):674-84

Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143, USA. Electronic address:

Neoplastic transformation requires changes in cellular identity. Emerging evidence increasingly points to cellular reprogramming, a process during which fully differentiated and functional cells lose aspects of their identity while gaining progenitor characteristics, as a critical early step during cancer initiation. This cell identity crisis persists even at the malignant stage in certain cancers, suggesting that reactivation of progenitor functions supports tumorigenicity. Here, we review recent findings that establish the essential role of cellular reprogramming during neoplastic transformation and the major players involved in it with a special emphasis on pancreatic cancer.
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http://dx.doi.org/10.1016/j.devcel.2015.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692359PMC
December 2015

SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors.

Sci Rep 2015 Apr 29;5:9841. Epub 2015 Apr 29.

1] Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA [2] Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA.

Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers.
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http://dx.doi.org/10.1038/srep09841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413894PMC
April 2015

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.

Genes Dev 2015 Mar;29(6):658-71

Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;

Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA.
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http://dx.doi.org/10.1101/gad.256628.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378197PMC
March 2015

The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma.

Nat Cell Biol 2014 Mar 23;16(3):255-67. Epub 2014 Feb 23.

Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA.

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.
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http://dx.doi.org/10.1038/ncb2916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684081PMC
March 2014

DDB2 suppresses epithelial-to-mesenchymal transition in colon cancer.

Cancer Res 2013 Jun 22;73(12):3771-82. Epub 2013 Apr 22.

Department of Biochemistry and Molecular Genetics; Center of Molecular Biology of Oral Diseases College of Dentistry, Cancer Center; and Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial-to-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here, we show that the xeroderma pigmentosum group E (XPE) gene product, damaged DNA-binding protein (DDB)-2, is downregulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-4069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686976PMC
June 2013

Tumor regression by phenethyl isothiocyanate involves DDB2.

Cancer Biol Ther 2013 Feb 31;14(2):108-16. Epub 2012 Oct 31.

Department of Biochemistry and Molecular Genetics, Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.

Phenethyl isothiocyanate (PEITC) is a promising cancer chemopreventive agent commonly found in edible cruciferous vegetables. It has been implicated also for therapy, and is in clinical trial for lung cancer. Here, we provide evidence that the tumor suppressive effect of PEITC is related to its ability to induce expression of damaged DNA binding protein 2 (DDB2), a DNA repair protein involved also in apoptosis and premature senescence. DDB2 expression is attenuated in a wide variety of cancers including the aggressive colon cancers. We show that, in colon cancer cells, reactive oxygen species, which are induced by PEITC, augment expression of DDB2 through the p38MAPK/JNK pathway, independently of p53. PEITC-induced expression of DDB2 is critical for inhibition of tumor progression by PEITC. Tumors derived from DDB2-deficient colon cancer cells are refractory to PEITC-treatments, resulting from deficiencies in apoptosis and senescence. The DDB2-proficient tumors, on the other hand, respond effectively to PEITC. The results show that PEITC can be used to induce expression of DDB2, and that expression of DDB2 is critical for effective response of tumors to PEITC.
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http://dx.doi.org/10.4161/cbt.22631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571992PMC
February 2013

Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence.

Int J Mol Sci 2012 5;13(9):11012-26. Epub 2012 Sep 5.

Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois at Chicago, 900 S. Ashland Ave, Chicago, IL 60607, USA; E-Mail:

Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.
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http://dx.doi.org/10.3390/ijms130911012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472727PMC
October 2015

p21 cooperates with DDB2 protein in suppression of ultraviolet ray-induced skin malignancies.

J Biol Chem 2012 Jan 13;287(5):3019-28. Epub 2011 Dec 13.

Department of Biochemistry and Molecular Genetics, Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

Exposure to ultraviolet rays (UV) in sunlight is the main cause of skin cancer. Here, we show that the p53-induced genes DDB2 and p21 are down-regulated in skin cancer, and in the mouse model they functionally cooperate to prevent UV-induced skin cancer. Our previous studies demonstrated an antagonistic role of DDB2 and p21 in nucleotide excision repair and apoptosis. Surprisingly, we find that the loss of p21 restores nucleotide excision repair and apoptosis in Ddb2(-/-) mice, but it does not protect from UV-mediated skin carcinogenesis. In contrast, Ddb2(-/-)p21(-/-) mice are significantly more susceptible to UV-induced skin cancer than the Ddb2(-/-) or the p21(-/-) mice. We provide evidence that p21 deletion in the Ddb2(-/-) background causes a strong increase in cell proliferation. The increased proliferation in the Ddb2(-/-)p21(-/-) background is related to a severe deficiency in UV-induced premature senescence. Also, the oncogenic pro-proliferation transcription factor FOXM1 is overexpressed in the p21(-/-) background. Our results show that the anti-proliferative and the pro-senescence pathways of DDB2 and p21 are critical protection mechanisms against skin malignancies.
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http://dx.doi.org/10.1074/jbc.M111.295816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270959PMC
January 2012

Cul4A is essential for spermatogenesis and male fertility.

Dev Biol 2011 Apr 1;352(2):278-87. Epub 2011 Feb 1.

Department of Biochemistry and Molecular Genetics (M/C 669), University of Illinois, College of Medicine, 900 S. Ashland Ave, Chicago, IL-60607, USA.

The mammalian Cul4 genes, Cul4A and Cul4B, encode the scaffold components of the cullin-based E3 ubiquitin ligases. The two Cul4 genes are functionally redundant. Recent study indicated that mice expressing a truncated CUL4A that fails to interact with its functional partner ROC1 exhibit no developmental phenotype. We generated a Cul4A-/- strain lacking exons 4-8 that does not express any detectable truncated protein. In this strain, the male mice are infertile and exhibit severe deficiencies in spermatogenesis. The primary spermatocytes are deficient in progression through late prophase I, a time point when expression of the X-linked Cul4B gene is silenced due to meiotic sex chromosome inactivation. Testes of the Cul4A-/- mice exhibit extensive apoptosis. Interestingly, the pachytene spermatocytes exhibit persistent double stranded breaks, suggesting a deficiency in homologous recombination. Also, we find that CUL4A localizes to the double stranded breaks generated in pre-pachytene spermatocytes. The observations identify a novel function of CUL4A in meiotic recombination and demonstrate an essential role of CUL4A in spermatogenesis.
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http://dx.doi.org/10.1016/j.ydbio.2011.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065526PMC
April 2011

DDB2, an essential mediator of premature senescence.

Mol Cell Biol 2010 Jun 29;30(11):2681-92. Epub 2010 Mar 29.

Center of Molecular Biology of Oral Diseases (M/C 860), College of Dentistry, Cancer Center, University of Illinois at Chicago, 801 S. Paulina Ave., Chicago, IL 60612, USA.

Reactive oxygen species (ROS) is critical for premature senescence, a process significant in tumor suppression and cancer therapy. Here, we reveal a novel function of the nucleotide excision repair protein DDB2 in the accumulation of ROS in a manner that is essential for premature senescence. DDB2-deficient cells fail to undergo premature senescence induced by culture shock, exogenous oxidative stress, oncogenic stress, or DNA damage. These cells do not accumulate ROS following DNA damage. The lack of ROS accumulation in DDB2 deficiency results from high-level expression of the antioxidant genes in vitro and in vivo. DDB2 represses antioxidant genes by recruiting Cul4A and Suv39h and by increasing histone-H3K9 trimethylation. Moreover, expression of DDB2 also is induced by ROS. Together, our results show that, upon oxidative stress, DDB2 functions in a positive feedback loop by repressing the antioxidant genes to cause persistent accumulation of ROS and induce premature senescence.
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http://dx.doi.org/10.1128/MCB.01480-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876515PMC
June 2010

DDB2 (damaged-DNA binding protein 2) in nucleotide excision repair and DNA damage response.

Cell Cycle 2009 Dec 17;8(24):4067-71. Epub 2009 Dec 17.

Department of Biochemistry and Molecular Genetics (M/C 669), Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.

DDB2 was identified as a protein involved in the Nucleotide Excision Repair (NER), a major DNA repair mechanism that repairs UV damage to prevent accumulation of mutations and tumorigenesis. However, recent studies indicated additional functions of DDB2 in the DNA damage response pathway. Herein, we discuss the proposed mechanisms by which DDB2 activates NER and programmed cell death upon DNA damage through its E3 ligase activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107032PMC
http://dx.doi.org/10.4161/cc.8.24.10109DOI Listing
December 2009

DDB2 decides cell fate following DNA damage.

Proc Natl Acad Sci U S A 2009 Jun 16;106(26):10690-5. Epub 2009 Jun 16.

Department of Biochemistry and Molecular Genetics (M/C 669), Cancer Center, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.

The xeroderma pigmentosum complementation group E (XP-E) gene product damaged-DNA binding protein 2 (DDB2) plays important roles in nucleotide excision repair (NER). Previously, we showed that DDB2 participates in NER by regulating the level of p21(Waf1/Cip1). Here we show that the p21(Waf1/Cip1) -regulatory function of DDB2 plays a central role in defining the response (apoptosis or arrest) to DNA damage. The DDB2-deficient cells are resistant to apoptosis in response to a variety of DNA-damaging agents, despite activation of p53 and the pro-apoptotic genes. Instead, these cells undergo cell cycle arrest. Also, the DDB2-deficient cells are resistant to E2F1-induced apoptosis. The resistance to apoptosis of the DDB2-deficient cells is caused by an increased accumulation of p21(Waf1/Cip1) after DNA damage. We provide evidence that DDB2 targets p21(Waf1/Cip1) for proteolysis. The resistance to apoptosis in DDB2-deficient cells also involves Mdm2 in a manner that is distinct from the p53-regulatory activity of Mdm2. Our results provide evidence for a new regulatory loop involving the NER protein DDB2, Mdm2, and p21(Waf1/Cip1) that is critical in deciding cell fate (apoptosis or arrest) upon DNA damage.
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http://dx.doi.org/10.1073/pnas.0812254106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2705559PMC
June 2009

Ectopic pregnancy--an analysis of 180 cases.

J Indian Med Assoc 2007 Jun;105(6):308, 310, 312 passim

Departmeht of Obstetrics and Gynaecology, NRS Medical College, Kolkata.

Ectopic pregnancy is the most life threatening emergency in pregnancy. Increase in incidence and impairment in fertility are now the real concerns. The aim of this study was to estimate the epidemiological, diagnostic and therapeutic aspects of ectopic pregnancy with a view to suggest action to improve the prognosis. This was a prospective study carried out at NRS Medical College, Kolkata, among consecutive 180 patients of ectopic pregnancy admitted from January, 2002 to December, 2004. During this period the incidence of ectopic pregnancy was 1 in 161(0.6%). The peak age of incidence was 26-30 years; primi were the most sufferers. There were 65.0% patients was had identifiable risk factors. Tubectomy (14.4%), history of abortion (26.1%), infertility (12.2%), pelvic inflammatory diseases (12.8%) and history of previous surgery (11.1%) were the important risk factors. Amenorrhoea (76.1%), abdominal pain (86.1%) and vaginal bleeding (42.2%) were the frequent presenting complaints. There were 87.8% patients was had pallor, 9.4% were admitted with features of shock. Cervical motion tenderness (82.2%) was the most frequent sign. Urinary beta-hCG was positive in 96.1% cases. Ultrasonography revealed diagnosis in 2/3rds cases among 129 patients. Culdocentesis evoked the diagnosis in 73.3% cases out of 135 patients. In 95.0% cases it was of tubal variety, 70.2% ruptured, 19.9% tubal abortion and 9.9% unruptured. Surgery by open method in the form of salpingectomy (81.9%), salpingo-oophorectomy (9.3%) and salpingostomy (5.3%) were the mainstay of management. Expectant management and medical therapy can be offered only in 1.2% and 1.75% respectively. There was no case fatality. By reducing and identifying the risk factors and 'catching' the patients at the earliest it is possible to improve the prognosis so far as morbidity, mortality and fertility are concerned.
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June 2007
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