WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase.
WISP-1 (Wnt-1-induced secreted protein) was identified as an oncogene regulated by the Wnt-1-beta-catenin pathway. WISP-1 belongs to the CCN family of growth factors, which are cysteine-rich, heparin-binding, secreted proteins associated with the extracellular matrix, and can interact with cellular integrins. Expression of WISP-1 in some cells results in transformation and tumorigenesis. Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. It also is demonstrated that WISP-1 can prevent cells from undergoing apoptosis following DNA damage through inhibition of the mitochondrial release of cytochrome c and up-regulation of antiapoptotic Bcl-X(L). Furthermore, the results show that WISP-1 protects cells from p53-dependent cell death, but not Fas-ligand activated cell death, suggesting that there may be cross talk between the tumor suppressor protein p53 and WISP-1 signaling pathways. WISP-1 acts to block cell death at a late stage in the p53-mediated apoptosis pathway.
Su
Fei
F
Laboratory of Cancer Biology, The Rockefeller University, New York, New York 10021-6399, USA.
Overholtzer
Michael
M
Besser
Daniel
D
Levine
Arnold J
AJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D055511:CCN Intercellular Signaling Proteins; D002460:Cell Line; D003574:Cytochrome c Group / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D003574:Cytochrome c Group; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein