Bcl-2 BH4 domain-induced gene expression profiles
JHU ID: C12295
Abstract:
Bcl-2 is a validated target for cancer therapies. Current small molecule drug inhibitors mimic the BH3 domain of pro-apoptotic Bcl-2 family members, binding to a pocket composed mainly of Bcl-2 homology (BH) domains 1-3, and only partially BH4. Surprisingly, while these agents are effective inducers of apoptosis, they do not inhibit the oncogenic functions of the BH4 domain. The BH4 domain is essential for the antiapoptotic functions of Bcl-2, and appears to mediate interactions with proteins not part of the Bcl-2 family. This explains the small but significant body of evidence supporting an oncogenic signaling role for Bcl-2 driven by the BH4 domain.
The full extent of the non-apoptotic roles of Bcl-2, including the contribution of the BH4 domain, has yet to be clarified. Our work aims to address this in prostate cancer cells, developing and utilizing a system that will implicate both the full length gene product and the BH4 domain.
Tangible Material Generated
Johns Hopkins researchers successfully generated human prostate cancer cells stably overexpressing Bcl-2 and the Bcl-2 BH4 domain. These clones displayed enhanced resistance to apoptosis induction. Bcl-2 overexpression also induced expression profile changes in these clones. This was mimicked by expression of the BH4 domain alone. We have developed a useful system to help enhance our understanding of Bcl-2 by highlighting changes in RNA expression profiles induced by the gene’s overexpression. We also show that the BH4 domain drives much of this function. The mechanisms responsible for these Bcl-2/BH4-induced changes warrant further investigation.
STAGE OF DEVELOPMENT
Tangible material, human prostate cancer cells stably overexpressing Bcl-2 and the Bcl-2 BH4 domain. The clones were validated for protein expression by western blot prior to a determination of classical functionality by treatment with apoptosis-inducing agents. RNA was then isolated from the clones for expression array analysis.
Associated Publications: AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1723. doi:10.1158/1538-7445.AM2013-1723
Disease Indication: Prostate Cancer
Technology Classification: Discovery/Research Tools
