The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts.
The MUC1 transmembrane glycoprotein is overexpressed by most human carcinomas. Overexpression of MUC1 confers transformation; however, the signaling pathways activated by this oncoprotein are largely unknown. The present studies demonstrated that MUC1-induced transformation of 3Y1 fibroblasts is associated with increased levels of phospho-Akt and phospho-Bad. The finding that LY294002 blocks MUC1-mediated increases in phospho-Akt and phospho-Bad supports the involvement of phosphoinositide 3-kinase (PI3K) as an upstream effector of this response. We also show that MUC1 increases the expression of the anti-apoptotic Bcl-x(L) protein (but not Bcl-2) by a PI3K-independent mechanism. In concert with these results, MUC1 attenuated (i) the loss of mitochondrial transmembrane potential, (ii) mitochondrial cytochrome c release, (iii) activation of caspase-9, and (iv) induction of apoptosis by the antimetabolite, 1-beta-d-arabinofuranosylcytosine. Similar results were obtained with the anti-cancer agent, gemcitabine. These findings indicate that expression of MUC1 in 3Y1 cells activates the anti-apoptotic PI3K/Akt and Bcl-x(L) pathways.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Deepak
D
Raina
Surender
S
Kharbanda
Donald
D
Kufe
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D018396:Mucin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases