BCL2 is a downstream effector of MIZ-1 essential for blocking c-MYC-induced apoptosis.

Publication/Presentation Date

1-5-2007

Abstract

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.

Volume

282

Issue

1

First Page

5

Last Page

13

ISSN

0021-9258

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

17082179

Department(s)

Administration and Leadership

Document Type

Article

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