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Molecular mechanisms involved in the nuclear receptor corepressor (N-CoR), and implications for normal proliferation and tumor organogenesis

Kristen Jepsen

Appointment Period: 2002-2003 / Grant Year: [18]

During this training period, I have focused my efforts on understanding the role of the transcriptional corepressors, N-CoR and SMRT, in cell proliferation and differentiation, including their role in prostate cancer. Using N-CoR gene-deleted mice, we found that neural stem cells lacking N-CoR proliferate poorly and prematurely differentiate down an astrocyte-like pathway. We also defined a critical role for N-CoR in conferring antagonist fuction to the selective androgen receptor modulators (SARMs) casodex and cyproterone acetate (CPA), drugs used in the treatment of prostate cancer. This implicates N-CoR as an important player in prostate cancer. Studies on mice gene-deleted for SMRT revealed defects in development of heart, brain, pituitary, secondary palate, thymus and olfactory bulb. I have focused on the role of SMRT in heart development, and found that the defect is similar to that reported for RXRalpha, a transcription factor partner of SMRT. Both RXRalpha and SMRT knock-out mice have thinned ventricular walls and ventricular septal defects, likely the result of decreased proliferation and aberrant differentiation of the myocytes in the ventricular wall. Preliminary data suggests that SMRT is required in a non-cell autonomous fashion in the epicardium rather than myocardium. Together, the research conducted during this training period has strengthened the hypothesis that N-CoR and SMRT are critical growth regulatory genes, influencing the delicate balance between proliferation and differentiation. This has implications for many types of cancer, as the uncontrolled growth of a cancer occurs when this balance is disrupted.

Jepsen K, Rosenfeld MG. Biological roles and mechanistic actions of co-repressor complexes. J Cell Sci. (2002) 115(Pt 4):689-98. PubMed PMID: 11865025.

Hermanson O, Jepsen K, Rosenfeld MG. N-CoR controls differentiation of neural stem cells into astrocytes. Nature. (2002) 419:934-9. PMID: 12410313.

Wagner BL, Valledor AF, Shao G, Daige CL, Bischoff ED, Petrowski M, Jepsen K, Baek SH, Heyman RA, Rosenfeld MG, Schulman IG, Glass CK. Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol Cell Biol. (2003) 23:5780-9. PMID: 12897148; PMCID: PMC166346.

Ogawa S, Lozach J, Jepsen K, Sawka-Verhelle D, Perissi V, Sasik R, Rose DW, Johnson RS, Rosenfeld MG, Glass CK. A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation. Proc Natl Acad Sci USA. (2004) 101:14461-6. PMID: 15452344; PMCID: PMC521940.