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Disruption of D-cyclin transcriptional regulation of the Androgen Receptor: Mechanism and Consequence

Olshavsky, Nicholas
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273168605

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
The family of D-cyclins has long been appreciated for their kinase-dependent role in cell cycle progression, however, a great body of work is dedicated to identifying targets that succumb to kinase-independent D-cyclin modulation. The nuclear receptor superfamily, including the androgen receptor (AR), is the largest group of proteins targeted by the D-cyclins. Within prostate cancer cells, excessive accumulation of the D-cyclins functionally represses subsequent AR signaling. Previously, two mechanisms by which cyclin D1a mediated repression of AR activity have been shown. Here, the mechanism by which cyclin D3 represses AR activity and AR-dependent proliferation was delineated and shown to behave similarly to that of cyclin D1a with subtle differences detected. Analyses of clinical specimens revealed perturbations of cyclin D3 expression and localization providing evidence that disruption of AR control by the D-cyclins could promote disease progression. One mechanism by which cyclin D1a control of AR is lost in tumors, is through the production of cyclin D1b, a splice variant that has diminished abilities to regulate AR activity and actually bolsters AR-dependent proliferation. The data presented within identify ASF/SF2 as an allele-specific effector for cyclin D1b in the prostate. In summary, disruption of AR control by the D-cyclins is one mechanism that can promote disease progression and indicates that additional studies are needed to fully examine how exploitation of this regulation could be utilized for the potential of therapeutic advances.
Linda Parysek, PhD (Committee Chair)
Karen Knudsen, PhD (Committee Member)
Peter Stambrook, PhD (Committee Member)
Jinsong Zhang, PhD (Committee Member)
Shuk-Mei Ho, PhD (Committee Member)
James Bruzik, PhD (Committee Member)
Jeff Molkentin, PhD (Committee Member)
189 p.
Cellular Biology
prostate cancer; cyclin D1; cyclin D1b; splicing; ASF/SF2; cyclin D3

Recommended Citations

Citations

  • Olshavsky, N. (2010). Disruption of D-cyclin transcriptional regulation of the Androgen Receptor: Mechanism and Consequence [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273168605

    APA Style (7th edition)

  • Olshavsky, Nicholas. Disruption of D-cyclin transcriptional regulation of the Androgen Receptor: Mechanism and Consequence. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273168605.

    MLA Style (8th edition)

  • Olshavsky, Nicholas. "Disruption of D-cyclin transcriptional regulation of the Androgen Receptor: Mechanism and Consequence." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273168605

    Chicago Manual of Style (17th edition)

ucin1273168605
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© 2010, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.