The RAS signaling pathway controls cell growth, survival and death in all multicellular organisms. Deregulation of RAS proto-oncogenes is found in approximately 30% of human cancer. Thus an important goal in cancer biology is to understand the molecular mechanisms underlying normal and aberrant RAS signals. Drosophila R7 photoreceptor cell fate specification is a genetically tractable model in which to study RAS signal transduction. In this system, we have shown that RAS activation directs a ubiquitin-mediated proteolysis pathway mediated by SEVEN-IN-ABSENTIA (SINA). SINA encodes a member of a highly conserved family of E3 ubiquitin ligases and has been implicated in neuronal differentiation, apoptosis, stress response, tumor suppression, beta-catenin, APC and p53 signaling in vertebrates. The substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligases, and the focus of our proposal is the SINA E3 ligase, an essential downstream component of RAS signaling pathway in Drosophila. The objectives of this research proposal are (1) to determine the developmental roles and regulation of SINA E3 family-dependent proteolysis in RAS signaling using Drosophila as a model organism, (2) to identify new SINA pathway components and determine their function in regulated proteolysis in RAS signal transduction, and (3) to investigate the roles of the mammalian SINA homologues (SIAHs) in RAS-mediated oncogenesis and to elucidate how the SIAH-dependent proteolysis promotes cell growth, differentiation and apoptosis during animal development and human cancers. Our central hypothesis is that the SINA-dependent proteolysis plays an important role in development. We will test this hypothesis by examining sina loss-of function phenotypes, by identifying new SINA pathway components by genetic screens and biochemical purification, and by determining their functions by a combination of genetic, molecular and biochemical analyses. We will also test the hypothesis that SIHA is required for RAS signal transduction during oncogenesis. We have detected enhanced expression of SINA in rapidly dividing cells during normal mammalian development and in human carcinomas, suggesting that SINA may be required for RAS-mediated cell proliferation in carcinogenesis. We propose to identify the function and regulation of SINA proteins in Drosophila, and apply what we have learned to human pancreatic cancer cells. Since many known SINA substrates have a demonstrated role in oncogenesis, it is likely that the proposed research will identify novels targets for anticancer therapies and contribute to our understanding of cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM069922-06S1
Application #
8208367
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Anderson, James J
Project Start
2009-09-30
Project End
2011-04-30
Budget Start
2010-01-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$30,082
Indirect Cost
Name
Eastern Virginia Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Pepper, Ian J; Van Sciver, Robert E; Tang, Amy H (2017) Phylogenetic analysis of the SINA/SIAH ubiquitin E3 ligase family in Metazoa. BMC Evol Biol 17:182
Jin, Xin; Pan, Yunqian; Wang, Liguo et al. (2017) Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction. Cancer Res 77:4328-4341
van Reesema, Lauren L Siewertsz; Zheleva, Vasilena; Winston, Janet S et al. (2016) SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. EBioMedicine 11:183-198
Siewertsz van Reesema, Lauren L; Lee, Michael P; Zheleva, Vasilena et al. (2016) RAS pathway biomarkers for breast cancer prognosis. Clin Lab Int 40:18-23
Burket, Jessica A; Benson, Andrew D; Tang, Amy H et al. (2015) NMDA receptor activation regulates sociability by its effect on mTOR signaling activity. Prog Neuropsychopharmacol Biol Psychiatry 60:60-5
Qin, R; Smyrk, T C; Reed, N R et al. (2015) Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1? pathway to predict survival in resectable pancreatic cancer. Br J Cancer 112:514-22
Burket, Jessica A; Benson, Andrew D; Tang, Amy H et al. (2014) Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders. Brain Res Bull 100:70-5
Deutsch, Stephen I; Tang, Amy H; Burket, Jessica A et al. (2014) NMDA receptors on the surface of cancer cells: target for chemotherapy? Biomed Pharmacother 68:493-6
Burket, Jessica A; Benson, Andrew D; Tang, Amy H et al. (2013) D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res Bull 96:62-70
Tang, Amy H (2011) Are you my friends or are you my enemies? Self Nonself 2:142-146

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