Regulation of the pro-apoptotic BH3-only protein Bim
BIM is a pro-apoptotic BH3-only protein that induces the ‘Bcl-2-regulated’ apoptotic pathway in response to various stimuli, including DNA damage, cytokine deprivation and several anti-cancer drugs. Accordingly, loss of Bim facilitates development of autoimmunity, neurodegenerative diseases and cancers.
Since Bim can be activated by a plethora of different stress signals, Bim expression must underlie tight regulation to ensure normal cell development and homeostasis. Several transcriptional, post-transcriptional and post-translational regulatory mechanisms have been described over the past years but only a few have been verified in a physiological context.
We generated data that refute a role of the previously accepted transcription factor FOXO3a in the regulation of Bim in the hematopoietic system.
Furthermore, we used reporter-based assays that led to the identification of a CCCH Zinc finger protein as a potential novel post-transcriptional regulator of Bim. Lastly, we found that growth factor-mediated post-translational regulation of BIM facilitates resistance to anti-cancer drugs in human melanoma cell lines expressing the activating mutant form of B-Raf.
Understanding underlying molecular processes of Bim regulation will enable us to improve treatment strategies for diseases that are caused by deregulated Bim.