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May 22, 2008

Scientists Link Protein-Degradation Ligase to Growth Control

  • Researchers identified a pivotal role for the CUL7 E3 ubiquitin ligase in growth control. CUL7 E3 is already known to play a critical role in mediating selective degradation of target proteins.

    The investigators found that the CUL7 E3 ligase targeted the insulin receptor substrate 1 (IRS-1) for ubiquitin-mediated degradation. They also observed that IRS-1 accumulated in CUL7-deficient cells. IRS-1 is a mediator of the insulin/insulin-like growth factor 1 signaling system and has a role in organismal growth and aging. Further, CUL7-mediated IRS-1 degradation required the activity of mammalian target of rapamycin (mTOR), a master regulator of cell growth.

    The scientists also discovered that CUL7-deficient cells exhibited multiple biochemical and morphological characteristics associated with senescent cells, specifically with oncogene-induced senescence, an antiproliferative program that is initiated by tumor suppressors in response to oncogenic activation of hyperproliferation.

    “Our working hypothesis is that aberrant accumulation of IRS-1, resulting from inactivation of the CUL7 E3, is an oncogenic stimulus that triggers cellular senescence, presumably through sustained MAPK activation and/or increased Akt signaling, both of which were previously shown to induce senescence,” explains  Zhen-Qiang Pan, Ph.D., associate professor of oncological science at Mount Sinai School of Medicine.

    Dr. Pan and colleagues at Mount Sinai performed this study in collaboration with investigators at Indiana University School of Medicine. The results will be published in the May 23 issue of Molecular Cell.



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