Medicine and Health Sciences Commons^™

Cd2ap Regulates Sumoylation Of Cin85 In Podocytes, Irini Tossidou, Rainer Niedenthal, Malte Klaus, Beina Teng, Kirstin Worthmann, Benjamin King, Kevin Peterson

Dartmouth Scholarship

Podocytes are highly differentiated and polarized epithelial cells located on the visceral side of the glomerulus. They form an indispensable component of the glomerular filter, the slit diaphragm, formed by several transmembrane proteins and adaptor molecules. Disruption of the slit diaphragm can lead to massive proteinuria and nephrotic syndrome in mice and humans. CD2AP is an adaptor protein that is important for the maintenance of the slit diaphragm. Together with its paralogue, CIN85, CD2AP belongs to a family of adaptor proteins that are primarily described as being involved in endocytosis and downregulation of receptor tyrosine kinase activity. We have shown …

Histone Deacetylase Inhibitor Valproic Acid Suppresses The Growth And Increases The Androgen Responsiveness Of Prostate Cancer Cells., Yu-Wei Chou, Nagendra K. Chaturvedi, Shougiang Ouyang, Fen-Fen Lin, Dharam Kaushik, Jue Wang, Isaac Kim, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

We identified the molecular target by histone deacetylase (HDAC) inhibitors for exploring their potential prostate cancer (PCa) therapy. Upon HDAC inhibitors-treatment, LNCaP cell growth was suppressed, correlating with increased cellular prostatic acid phosphatase (cPAcP) expression, an authentic protein tyrosine phosphatase. In those cells, ErbB-2 was dephosphorylated, histone H3/H4 acetylation and methylation increased and cyclin proteins decreased. In PAcP shRNA-transfected C-81 cells, valproic acid (VPA) efficacy of growth suppression was diminished. Further, VPA pre-treatment enhanced androgen responsiveness of C-81, C4-2 and MDA PCa2b-AI cells. Thus, cPAcP expression is involved in growth suppression by HDAC inhibitors in PCa cells, and VPA pre-treatments …

Effect Of Protein Kinase C Delta (Pkc-Δ) Inhibition On The Transcriptome Of Normal And Systemic Sclerosis Human Dermal Fibroblasts In Vitro., Peter J Wermuth, Sankar Addya, Sergio A Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

Previous studies demonstrated that protein kinase C- δ (PKC-δ) inhibition with the selective inhibitor, rottlerin, resulted in potent downregulation of type I collagen expression and production in normal human dermal fibroblasts and abrogated the exaggerated type I collagen production and expression in fibroblasts cultured from affected skin from patients with the fibrosing disorder systemic sclerosis (SSc). To elucidate the mechanisms involved in the ability of PKC-δ to regulate collagen production in fibroblasts, we examined the effects of PKC-δ inhibition on the transcriptome of normal and SSc human dermal fibroblasts. Normal and SSc human dermal fibroblasts were incubated with rottlerin (5 …

The Raf/Mek/Extracellular Signal-Regulated Kinase 1/2 Pathway Can Mediate Growth Inhibitory And Differentiation Signaling Via Androgen Receptor Downregulation In Prostate Cancer Cells., Seung-Keun Hong, Jin-Hwan Kim, Ming-Fong Lin, Jong-In Park

Journal Articles: Biochemistry & Molecular Biology

Upregulated ERK1/2 activity is correlated with androgen receptor (AR) downregulation in certain prostate cancer (PCa) that exhibits androgen deprivation-induced neuroendocrine differentiation, but its functional relevance requires elucidation. We found that sustained ERK1/2 activation using active Raf or MEK1/2 mutants is sufficient to induce AR downregulation at mRNA and protein levels in LNCaP. Downregulation of AR protein, but not mRNA, was blocked by proteasome inhibitors, MG132 and bortezomib, indicating that the pathway regulation is mediated at multiple points. Ectopic expression of a constitutively active AR inhibited Raf/MEK/ERK-mediated regulation of the differentiation markers, neuron-specific enolase and neutral endopeptidase, and the cyclin-dependent kinase …

Pathobiological Implications Of Muc16 Expression In Pancreatic Cancer., Dhanya Haridas, Subhankar Chakraborty, Moorthy P. Ponnusamy, Imayavaramban Lakshmanan, Satyanarayana Rachagani, Eric Cruz, Sushil Kumar, Srustidhar Das, Subodh M. Lele, Judy M. Anderson, Uwe A. Wittel, Michael A. Hollingsworth, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

MUC16 (CA125) belongs to a family of high-molecular weight O-glycosylated proteins known as mucins. While MUC16 is well known as a biomarker in ovarian cancer, its expression pattern in pancreatic cancer (PC), the fourth leading cause of cancer related deaths in the United States, remains unknown. The aim of our study was to analyze the expression of MUC16 during the initiation, progression and metastasis of PC for possible implication in PC diagnosis, prognosis and therapy. In this study, a microarray containing tissues from healthy and PC patients was used to investigate the differential protein expression of MUC16 in PC. MUC16 …

Human Rna Polymerase Ii-Association Factor 1 (Hpaf1/Pd2) Regulates Histone Methylation And Chromatin Remodeling In Pancreatic Cancer., Parama Dey, Moorthy P. Ponnusamy, Shonali Deb, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Change in gene expression associated with pancreatic cancer could be attributed to the variation in histone posttranslational modifications leading to subsequent remodeling of the chromatin template during transcription. However, the interconnected network of molecules involved in regulating such processes remains elusive. hPaf1/PD2, a subunit of the human PAF-complex, involved in the regulation of transcriptional elongation has oncogenic potential. Our study explores the possibility that regulation of histone methylation by hPaf1 can contribute towards alteration in gene expression by nucleosomal rearrangement. Here, we show that knockdown of hPaf1/PD2 leads to decreased di- and tri-methylation at histone H3 lysine 4 residues in …

Monoclonal Antibodies Recognizing The Non-Tandem Repeat Regions Of The Human Mucin Muc4 In Pancreatic Cancer., Maneesh Jain, Ganesh Venkatraman, Nicolas Moniaux, Sukhwinder Kaur, Sushil Kumar, Subhankar Chakraborty, Grish C. Varshney, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

The MUC4 mucin is a high molecular weight, membrane-bound, and highly glycosylated protein. It is a multi-domain protein that is putatively cleaved into a large mucin-like subunit (MUC4α) and a C-terminal growth-factor like subunit (MUC4β). MUC4 plays critical roles in physiological and pathological conditions and is aberrantly overexpressed in several cancers, including those of the pancreas, cervix, breast and lung. It is also a potential biomarker for the diagnosis, prognosis and progression of several malignancies. Further, MUC4 plays diverse functional roles in cancer initiation and progression as evident from its involvement in oncogenic transformation, proliferation, inhibition of apoptosis, motility and …

Marital Status And Survival In Pancreatic Cancer Patients: A Seer Based Analysis., Michael J. Baine, Freshta Sahak, Chi Lin, Subhankar Chakraborty, Surinder K. Batra, Elizabeth R. Lyden

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Recent findings suggest that marital status affects survival in patients with different types of cancer. However, its role in the survival of patients with pancreatic ductal adenocarcinoma is unknown. In this study, we investigated whether there was an association between marital status and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC).

METHODS: Adult patients diagnosed with PDAC between 1998 and 2003 with known marital statuses were identified from the Surveillance, Epidemiology, and End Results registry of the National Cancer Institute. OS for these patients was plotted using the Kaplan-Meier method. Comparative risks of mortality were evaluated by …

Tnfα Enhances The Motility And Invasiveness Of Prostatic Cancer Cells By Stimulating The Expression Of Selective Glycosyl- And Sulfotransferase Genes Involved In The Synthesis Of Selectin Ligands., Prakash Radhakrishnan, Vishwanath Chachadi, Ming-Fong Lin, Rakesh Singh, Reiji Kannagi, Pi-Wan Cheng

Journal Articles: Biochemistry & Molecular Biology

Sialyl Lewis x (sLe(x)) plays an important role in cancer metastasis. But, the mechanism for its production in metastatic cancers remains unclear. The objective of current study was to examine the effects of a proinflammatory cytokine on the expression of glycosyltransferase and sulfotransferase genes involved in the synthesis of selectin ligands in a prostate cancer cell line. Androgen-independent human lymph node-derived metastatic prostate cancer cells (C-81 LNCaP), which express functional androgen receptor and mimic the castration-resistant advanced prostate cancer, were used. TNFα treatment of these cells increased their binding to P-, E- and L-selectins, anti-sLe(x) antibody, and anti-6-sulfo-sialyl Lewis x …

Activated Krasg¹²D Is Associated With Invasion And Metastasis Of Pancreatic Cancer Cells Through Inhibition Of E-Cadherin., Satyanarayana Rachagani, S Senapati, S Chakraborty, Moorthy P. Ponnusamy, Sushil Kumar, Lynette Smith, Maneesh Jain, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Pancreatic cancer (PC) harbours an activated point mutation (Kras(G12D)) in the Kras proto-oncogene that has been demonstrated to promote the development of PC.

METHODS: This study was designed to investigate the effect of the oncogenic Kras(G12D) allele on aggressiveness and metastatic potential of PC cells. We silenced the oncogenic Kras(G12D) allele expression in CD18/HPAF and ASPC1 cell lines by stable expression of shRNA specific to the Kras(G12D)allele.

RESULTS: The Kras(G12D) knockdown cells exhibited a significant decrease in motility (P

CONCLUSIONS: The results of this study suggest that the Kras(G12D) allele promotes metastasis in PC cells partly through the downregulation …

Hedgehog Inhibition Promotes A Switch From Type Ii To Type I Cell Death Receptor Signaling In Cancer Cells., Satoshi Kurita, Justin L. Mott, Sophie C. Cazanave, Christian D. Fingas, Maria E. Guicciardi, Steve F. Bronk, Lewis R. Roberts, Martin E. Fernandez-Zapico, Gregory J. Gores

Journal Articles: Biochemistry & Molecular Biology

TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, …

Transcriptional Profiling Of Peripheral Blood Mononuclear Cells In Pancreatic Cancer Patients Identifies Novel Genes With Potential Diagnostic Utility., Michael J. Baine, Subhankar Chakraborty, Lynette M. Smith, Kavita Mallya, Aaron R. Sasson, Randall E. Brand, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility.

METHODS AND FINDINGS: PBMC samples from 26 PC patients and 33 matched healthy controls were …

Steroids Up-Regulate P66shc Longevity Protein In Growth Regulation By Inhibiting Its Ubiquitination., Santosh Kumar, Satyendra Kumar, Mythilypriya Rajendran, Syed Mahfuzul Alam, Fen-Fen Lin, Pi-Wan Cheng, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: p66Shc, an isoform of Shc adaptor proteins, mediates diverse signals, including cellular stress and mouse longevity. p66Shc protein level is elevated in several carcinomas and steroid-treated human cancer cells. Several lines of evidence indicate that p66Shc plays a critical role in steroid-related carcinogenesis, and steroids play a role in its elevated levels in those cells without known mechanism.

METHODS AND FINDINGS: In this study, we investigated the molecular mechanism by which steroid hormones up-regulate p66Shc protein level. In steroid-treated human prostate and ovarian cancer cells, p66Shc protein levels were elevated, correlating with increased cell proliferation. These steroid effects on …