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Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro
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MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage

Deepak Raina1, Rehan Ahmad, Shailendra Kumar

  • 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

The EMBO Journal
|August 5, 2006
PubMed

Insights

The MUC1 oncoprotein prevents nuclear targeting of c-Abl tyrosine kinase, inhibiting apoptosis in response to DNA damage. Mutating MUC1 disrupts this interaction, restoring apoptosis and potentially enhancing cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • The nonreceptor c-Abl tyrosine kinase translocates to the nucleus upon DNA damage, initiating apoptosis.
  • The MUC1 oncoprotein, overexpressed in carcinomas, inhibits apoptosis induced by genotoxic agents.

Purpose of the Study:

  • To investigate the mechanism by which MUC1 interferes with c-Abl nuclear translocation and apoptosis.
  • To elucidate the interaction between MUC1 and c-Abl in response to DNA damage.

Main Methods:

  • Utilized human carcinoma cells with manipulated MUC1 expression (gain and loss of function).
  • Investigated protein-protein interactions using techniques like SH2 domain binding assays.
  • Analyzed protein phosphorylation at specific sites (Tyr-60 and Thr-735).
  • Assessed the impact of MUC1 mutations on c-Abl function and apoptosis.

Main Results:

  • MUC1 abrogates the nuclear targeting of c-Abl in response to DNA damage via a MUC1-dependent mechanism.
  • c-Abl directly phosphorylates MUC1 at Tyr-60, forming a complex mediated by the c-Abl SH2 domain.
  • MUC1 binding to c-Abl inhibits c-Abl phosphorylation at Thr-735 and its interaction with 14-3-3 proteins.
  • A Tyr-60 MUC1 mutant disrupts MUC1-c-Abl interaction, restores c-Abl phosphorylation and 14-3-3 binding, and attenuates MUC1's antiapoptotic function.

Conclusions:

  • MUC1 sequesters c-Abl in the cytoplasm, thereby inhibiting apoptosis in response to genotoxic anticancer agents.
  • Targeting the MUC1-c-Abl interaction may represent a therapeutic strategy to restore apoptosis in MUC1-expressing carcinomas.

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