Bim, a Proapoptotic Protein, Up-regulated via Transcription Factor E2F1-dependent Mechanism, Functions as a Prosurvival Molecule in Cancer*

Background: The BH3-only protein Bim is conventionally considered a proapoptotic protein because it induces Bax/Bak oligomerization on mitochondria. Results: Bim is constitutively up-regulated in cancer cells via an E2F1-dependent mechanism. Silencing of Bim induces cancer cell apoptosis. Conclusion: Bim phosphorylation and its sequestration by prosurvival proteins Bcl-xL/Mcl-1 may suppress proapoptotic function of Bim. Significance: Bim may possess prosurvival functions in epithelial cancer cells. Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax/Bak-mediated cytochrome c release and apoptosis. Here, we provide evidence for a novel prosurvival function of Bim in cancer cells. Bim was constitutively overexpressed in multiple prostate and breast cancer cells as well as in primary tumor cells. Quantitative real time PCR analysis showed that Bim was transcriptionally up-regulated. We have identified eight endogenous E2F1-binding sites on the Bim promoter using in silico analysis. Luciferase assay demonstrated that Bim expression was E2F1-dependent as mutation of the E2F1-binding sites on the Bim promoter inhibited luciferase activities. In support, E2F1 silencing led to the loss of Bim expression in cancer cells. Bim primarily localized to mitochondrial and cytoskeleton-associated fractions. Bim silencing or microinjection of anti-Bim antibodies into the cell cytoplasm resulted in cell rounding, detachment, and subsequent apoptosis. We observed up-regulation of prosurvival proteins Bcl-xL and Mcl-1, which sequester Bim in cancer cells. In addition, a phosphorylated form of Bim was also elevated in cancer cells. These findings suggest that the constitutively overexpressed Bim may function as a prosurvival molecule in epithelial cancer cells, and phosphorylation and association with Bcl-xL/Mcl-1 block its proapoptotic functions.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-11-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M112.386102PMID 23152504PMCID PMC3537034
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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