PROSTATE CELL PROLIFERATION IN CANCER AND AGING
Principal Investigator: ANA SOTO
Abstract: Description: (Applicant's abstract) Prostate cancer is the most common cancer in American men. These cancer cells initially respond to androgen (A)-withdrawal, undergoing apoptosis and decreased cell proliferation. Later on, they overcome this inhibition and relapse. However, in addition to A-dependent proliferation and a total lack of A response, there is a prostate cancer phenotype whereby proliferation is inhibited by androgens (androgen-induced shutoff). Our research objective is to understand the molecular mechanisms underlying this phenomenon. The AS3 gene was identified as a candidate because its pattern of expression was consistent with that of a mediator of the proliferative shutoff. Functional evidence obtained using expression vectors containing AS3 demonstrated that AS3 triggers a proliferative shutoff. Conversely, antisense AS3 blocks the expression of the A-induced shutoff. The AS3 sequence seems to be a transcription factor with trans-activating protein recognition, and DNA binding domains; it also has a protein kinase motif. Alternatively, AS3 may behave by activating other proteins through phosphorylation, and/or by binding to them. The Specific Aims of this application are designed to elucidate the mechanisms by which AS3 inhibits cell proliferation. Aim #1: Exploring the hypothesis that AS3 is a transcription factor (identification of the downstream mediators of the proliferative shutoff). Aim #2: Investigating the hypothesis that AS3 activates effector proteins by phosphorylating them. Aim #3: Mapping the AS3 pathway. Testing the role of the putative downstream mediators identified in Aim #1 in the shutoff effect. Aim #4: Testing the hypothesis that AS3 expression arrests tumor growth by inoculation of tetracycline-regulated AS3 transfectants into nude mice. We expect that this research will lead to the development of markers to identify this phenotype, and to the development of specific therapeutic strategies.
Funding Period: 1993-09-30 - 2007-01-31
more information: NIH RePORT
- APRIN is a unique Pds5 paralog with features of a chromatin regulator in hormonal differentiationMaricel Maffini
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
J Steroid Biochem Mol Biol 108:32-43. 2008..The results indicate that APRIN, in addition to its Pds5 similarity, has the features and localization of a hormone-induced chromatin regulator...