Laboratories > Dr. Richard G. Pestell
Laboratories - Dr. Richard G. Pestell
Molecular mechanisms and gene therapy of breast and prostate cancer
Our research activities focus on understanding the mechanisms governing
cell-cycle regulated gene transcription and the role of these proteins in
tumorigenesis and differentiation. The cyclin D1 gene encodes a regulatory
subunit of a holoenzyme that phosphorylates and inactivates the tumor
suppressor protein pRB (retinoblastoma protein) resulting in release of the
pRB binding proteins and transcription factors, E2Fs. Several cyclin
dependent kinase inhibitors (CDKI), p16/p19 block this activity of cyclin
D1. Cyclin D1 plays a critical role in tumorigenesis and differentiation.
Because the abundance of the cyclin D1 gene is rate-limiting in progression
through the cell-cycle in cells that contain the pRB protein, we have
delineated the molecular mechanisms regulating the cyclin D1 gene. We
demonstrated that cyclin D1 kinase (CDK) activity and cyclin D1 promoter
activity is induced by oncogenes (p21ras, Rac, dbl, v-src, Neu-also known
as ErbB-2), growth factors and G-protein coupled receptors. The
transcription factors (E2Fs,JUN/Fos, CREB, ATF2/ETS), coactivators
(p300/CBP,Brg/Brm1) and scaffolding proteins (JIP1, caveolins) coordinate
this induction.
Using retroviral and lentiviral expression systems we are examining the
requirement for specific cyclins and CKI for induction and progression of
breast and prostate tumors induced by oncogenes. These systems are used to
examine treatment synergy with conventional therapies.
We have developed tissue-specific inducible transgenic expression systems
and are using this transgenic approach to examine the role of cyclin D1, the
CDKI in breast and prostate cancer.
Using knockout mice we are examining the role of CDKI in breast cancer
induced by specific oncogenes and synergy with conventional therapies.
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