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hMad4, c-Myc endogenous inhibitor, induces a replicative senescence-like state when overexpressed in human

Richard Marcotte1, Jing-Fang Qian, James Chen

  • 1The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B Davis-Jewish General Hospital and Department of Medicine, McGill University, Montréal, Québec, Canada.

Journal of Cellular Biochemistry
|May 23, 2003
PubMed

Insights

Human Mad4 (hMad4) protein inhibits cell proliferation and transformation by repressing Myc activity. hMad4 induces a senescence-like state in human fibroblasts, suggesting its role in regulating cellular aging.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Mad family proteins antagonize Myc-driven cell proliferation and transformation.
  • Understanding the role of Mad family members in cellular processes is crucial.

Purpose of the Study:

  • To isolate and characterize human Mad4 (hMad4).
  • To investigate the function of hMad4 in cell proliferation, transformation, and senescence.

Main Methods:

  • Isolation of human Mad4 (hMad4) cDNA.
  • Northern blot analysis to determine hMad4 expression patterns.
  • Reporter gene assays to assess hMad4's effect on Myc/Max activity.
  • Infection of human fibroblasts to observe phenotypic changes.

Main Results:

  • hMad4 shares high identity with mouse Mad4 and is expressed in various human tissues, notably brain, lung, and muscle.
  • hMad4 represses Myc/Max heterodimer activity on E-box elements.
  • hMad4 expression inhibits cell proliferation and clonogenic formation.
  • hMad4 infection induces a replicative senescence-like state in fibroblasts, marked by senescence-associated beta-galactosidase and PAI-1 expression.

Conclusions:

  • hMad4 functions as a repressor of Myc-dependent proliferation and transformation.
  • hMad4 plays a significant role in regulating replicative senescence in human cells.
Keywords:
Non-programmatic

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