MUC1 oncoprotein suppresses activation of the ARF-MDM2-p53 pathway.
The MUC1 oncoprotein interacts with the c-Abl tyrosine kinase and blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. Mutation of the MUC1 cytoplasmic domain at Tyr-60 disrupts the MUC1-c-Abl interaction. The present results demonstrate that the MUC1(Y60F) mutant is a potent inducer of the ARF tumor suppressor. MUC1(Y60F) induces transcription of the ARF locus by a c-Abl-dependent mechanism that promotes CUL-4A-mediated nuclear export of the replication protein Cdc6. The functional significance of these findings is that MUC1(Y60F)-induced ARF expression and thereby inhibition of MDM2 results in the upregulation of p53 and the homeodomain interacting protein kinase 2 (HIPK2) serine/threonine kinase. HIPK2-mediated phosphorylation of p53 on Ser-46 was further associated with a shift from expression of the cell cycle arrest-related p21 gene to the apoptosis-related PUMA gene. We also show that the MUC1(Y60F) mutant functions as dominant negative inhibitor of tumorigenicity. These findings indicate that the oncogenic function of MUC1 is conferred by suppressing activation of the ARF-MDM2-p53 pathway.
Raina
Deepak
D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Ahmad
Rehan
R
Chen
Dongshu
D
Kumar
Shailendra
S
Kharbanda
Surender
S
Kufe
Donald
D
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D045325:HCT116 Cells; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D018396:Mucin-1 / Q000235:genetics* / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
C060192:MUC1 protein, human; D018396:Mucin-1; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016315:Proto-Oncogene Proteins c-abl; D020823:ADP-Ribosylation Factor 1