CCAAT/enhancer binding proteins (C/EBPs) are highly conserved family of DNA binding proteins implicated in the transcriptional control of cell growth. The C/EBP-beta gene is unique in that it encodes a single mRNA that is translated into multiple proteins with opposing biological activities. The goal of this project is to investigate the role of C/EBP-beta translation products in mammary epithelial cell growth control. In nontransformed mammary epithelial cells the principal C/EBP-beta translation product is a full-length transcription activator (LAP, or liver-enriched activator protein ). LAP appears to function in the early G1 phase of the cell cycle. A second C/EBP-beta translation product is truncated and acts as a transcription inhibitor (LIP, or liver-enriched inhibitory protein ). LIP appears to function as a growth suppressor. LIP is a minor translation product in normal mammary epithelial cells, however, LIP levels are dramatically elevated in mammary tumors. Our hypothesis is that LAP functions as a growth activator and LIP functions as a growth suppressor in normal cells, but these functions are altered in transformed cells.
The specific aims of Phase I of this proposal will investigate the role of both LAP and LIP in normal mammary epithelial cell growth. Critical postranslational regulation (phosphorylation and dimerization) will also be investigated in normal mammary epithelial cells and in mammary tumors from MMTV/c-neu transgenic mice. More advanced analyses involving isolation of downstream effector genes will be undertaken in Phase II. The results will provide the breast cancer research community with a better understanding of the role of C/EBP-beta translation products in mammary epithelial cell growth regulation. Dr. Julie Hutt is an outstanding SERCA candidate. Dr. Hutt has demonstrated exceptional academic ability (BS/MS, Chemistry; DVM; all with highest academic honors). Dr. Hutt has completed her academic course work, PhD general exam and requirements for American College of Veterinary Pathology board certification. Dr. Hutt has demonstrated a strong commitment to a career as an independent academic investigator. The sponsor's lab will provide an excellent environment for developing technical skills in molecular biology and applying these skills to basic research problems in Comparative Pathology and Medicine. The Department of Veterinary Biosciences is a highly productive research-oriented professional training environment.
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|Hutt, Julie A; DeWille, James W (2002) Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway. Mol Cancer Ther 1:601-10|
|Dearth, L R; Hutt, J; Sattler, A et al. (2001) Expression and function of CCAAT/enhancer binding proteinbeta (C/EBPbeta) LAP and LIP isoforms in mouse mammary gland, tumors and cultured mammary epithelial cells. J Cell Biochem 82:357-70|
|Hutt, J A; O'Rourke, J P; DeWille, J (2000) Signal transducer and activator of transcription 3 activates CCAAT enhancer-binding protein delta gene transcription in G0 growth-arrested mouse mammary epithelial cells and in involuting mouse mammary gland. J Biol Chem 275:29123-31|
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