Controlled by a WISP

Abstract

Wnt1-induced secreted protein (WISP-1) is a member of the CCN family of growth factors [named for the founding members (connective tissue growth factor, cysteine rich-61, and nephroblastoma overexpressed)], which are secreted cysteine-rich, heparin-binding, and extracellular matrix-associated proteins. Su et al. showed that WISP-1 activated the serine-threonine protein kinase Akt, which has been implicated in cell survival pathways. Overexpression of WISP-1 inhibited apoptosis after treatments that induced DNA damage and produced a death signal dependent on the tumor suppressor and transcriptional regulator p53. WISP-1 did not promote cell survival when expressed with dominant-negative mutants of Akt or in cells deficient in p53. Protection by WISP-1 was specific for stimuli that activated apoptosis through the "intrinsic" pathway by release of cytochrome c from the mitochondria, and WISP-1 was ineffective for protecting cells from apoptosis due to activation of the death receptor Fas. Overexpression of WISP-1 did not appear to inhibit p53 activation or transcriptional activity directly. Instead, WISP-1-overexpressing cells expressed larger amounts of the anti-apoptotic protein Bcl-X L at rest than untransfected cells did, and cytochrome c release was inhibited in the WISP-1-overexpressing cells when they were subjected to DNA-damaging stimuli. Thus, WISP-1 is a growth factor that can trigger signals that inhibit cell death in response to internal signals. F. Su, M. Overholtzer, D. Besser, A. J. Levine, WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of Akt kinase. Genes Dev. 16 , 46-57 (2002). [Abstract] [Full Text]