Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis

Cell Cycle. 2008 May 1;7(9):1197-204. doi: 10.4161/cc.7.9.5886. Epub 2008 Mar 10.

Abstract

The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by gamma- radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Aging / metabolism
  • Aging / radiation effects
  • Aging, Premature / genetics
  • Aging, Premature / metabolism
  • Animals
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • CLOCK Proteins
  • Cell Proliferation / radiation effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Chronobiology Disorders / genetics*
  • Chronobiology Disorders / metabolism
  • Chronobiology Disorders / physiopathology
  • Circadian Rhythm / genetics*
  • Down-Regulation / genetics
  • Down-Regulation / radiation effects
  • Female
  • Gamma Rays / adverse effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Genetic Predisposition to Disease / genetics
  • Immunity, Innate / genetics
  • Immunity, Innate / radiation effects
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / radiation effects
  • Male
  • Mice
  • Mutation / genetics*
  • Phenotype
  • Trans-Activators / genetics*

Substances

  • Trans-Activators
  • CLOCK Proteins
  • Clock protein, mouse