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Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes

Debdutta Bandyopadhyay1, Nihal A Okan, Elise Bales

  • 1Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

Cancer Research
|November 5, 2002
PubMed

Insights

The histone acetyltransferase p300 is crucial for human melanocyte proliferation. Its depletion leads to reduced cyclin E gene expression and triggers senescence, highlighting p300

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Epigenetics

Background:

  • Histone acetyltransferases p300 and CBP are vital for cell proliferation, differentiation, and apoptosis.
  • These proteins regulate numerous transcription factors, impacting gene expression.
  • Cellular levels of p300 and CBP decrease with increasing population doublings in human melanocytes.

Purpose of the Study:

  • To investigate the role of p300 in regulating proliferation and senescence in melanocytes.
  • To elucidate the mechanism by which p300 influences cyclin E gene expression.
  • To determine the functional significance of p300 in melanocytic cell growth and aging.

Main Methods:

  • Quantification of p300 and CBP levels during melanocyte proliferation.
  • Analysis of cyclin E gene promoter activity using reporter assays.
  • Assessment of histone acetylation and recruitment of p300/HDAC1 to the cyclin E promoter.
  • Inhibition of p300 activity using dominant-negative mutants and chemical inhibitors (Lys-CoA).

Main Results:

  • p300 depletion caused transcriptional down-regulation of the cyclin E gene via histone deacetylation at its promoter.
  • p300 activated the cyclin E promoter, while pRB and a dominant-negative p300 mutant repressed it.
  • p300 and histone deacetylase 1 showed alternative recruitment to the cyclin E promoter in proliferating versus senescent melanocytes.
  • Inhibition of p300 activity led to growth inhibition, reduced cyclin E, and induced senescence markers in melanocytes and melanoma cells.

Conclusions:

  • p300 plays an essential role in regulating proliferation and senescence in melanocytic cells.
  • The study provides mechanistic insights into p300's function in controlling cell cycle progression and aging.
  • Targeting p300 activity may offer therapeutic strategies for melanoma and other proliferative disorders.

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