MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage.
The nonreceptor c-Abl tyrosine kinase binds to cytosolic 14-3-3 proteins and is targeted to the nucleus in the apoptotic response to DNA damage. The MUC1 oncoprotein is overexpressed by most human carcinomas and blocks the induction of apoptosis by genotoxic agents. Using human carcinoma cells with gain and loss of MUC1 function, we show that nuclear targeting of c-Abl by DNA damage is abrogated by a MUC1-dependent mechanism. The results demonstrate that c-Abl phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the c-Abl SH2 domain to the pTyr-60 site. Binding of MUC1 to c-Abl attenuates phosphorylation of c-Abl on Thr-735 and the interaction between c-Abl and cytosolic 14-3-3. We also show that expression of MUC1 with a mutation at Tyr-60 (i) disrupts the interaction between MUC1 and c-Abl, (ii) relieves the MUC1-induced block of c-Abl phosphorylation on Thr-735 and binding to 14-3-3, and (iii) attenuates the MUC1 antiapoptotic function. These findings indicate that MUC1 sequesters c-Abl in the cytoplasm and thereby inhibits apoptosis in the response to genotoxic anticancer agents.
Raina
Deepak
D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ahmad
Rehan
R
Kumar
Shailendra
S
Ren
Jian
J
Yoshida
Kiyotsugu
K
Kharbanda
Surender
S
Kufe
Donald
D
D048948:14-3-3 Proteins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D048948:14-3-3 Proteins; D018396:Mucin-1; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl