BCL2 is a downstream effector of MIZ-1 essential for blocking c-MYC-induced apoptosis.
The c-MYC oncoprotein is among the most potent transforming agents in human cells. Ironically, c-MYC is also capable of inducing massive apoptosis under certain conditions. A clear understanding of the distinct pathways activated by c-MYC during apoptosis induction and transformation is crucial to the design of therapeutic strategies aimed at selectively reactivating the apoptotic potential of c-MYC in cancer cells. We recently demonstrated that apoptosis induction in primary human cells strictly requires that c-MYC bind and inactivate the transcription factor MIZ-1. This presumably blocked the ability of MIZ-1 to activate the transcription of an unidentified pro-survival gene. Here we report that MIZ-1 activates the transcription of BCL2. More importantly, inhibition of the MIZ-1/BCL2 signal is an essential event during the apoptotic response. Furthermore, targeting BCL2 with short hairpin RNA or small molecule inhibitors restores the apoptotic potential of a c-MYC mutant that is defective for MIZ-1 inhibition. These observations suggest that repression of BCL2 transcription is the single essential consequence of targeting the MIZ-1 pathway during apoptosis induction. These data define a genetic pathway that helps to explain historical observations documenting cooperation between c-MYC and BCL2 overexpression in human cancer.
Patel
Jagruti H
JH
Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
McMahon
Steven B
SB
D017209:Apoptosis; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018274:Electroporation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C107961:ZBTB17 protein, human