The Circadian Clock Component BMAL1 Is a Critical Regulator of p21 Expression and Hepatocyte Proliferation

Dec 19, 2007The Journal of biological chemistry

The body’s internal clock protein BMAL1 controls cell growth by regulating p21 in liver cells

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Abstract

The cell cycle inhibitor p21WAF1/CIP1 is expressed in a circadian rhythm in mouse peripheral organs.

Rhythmic expression of p21WAF1/CIP1 mRNA and protein was observed in differentiated skeletal muscle cells after serum shock.
In clock-deficient Bmal1-/- mice, p21WAF1/CIP1 expression is significantly increased and loses its rhythmicity.
The transcription of p21WAF1/CIP1 is regulated by the opposing actions of specific nuclear receptors involved in the circadian clock.
Primary hepatocytes overexpressing p21WAF1/CIP1 showed a reduced proliferation rate.
Knockdown of p21WAF1/CIP1 using small interfering RNA reversed the decreased proliferation phenotype.

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Most living organisms show circadian (approximately 24 h) rhythms in physiology and behavior. These oscillations are generated by endogenous circadian clocks, present in virtually all cells where they control key biological processes. Although circadian gating of mitosis has been reported for many years in some peripheral tissues, the underlying molecular mechanisms have remained poorly understood. Here we show that the cell cycle inhibitor p21WAF1/CIP1 is rhythmically expressed in mouse peripheral organs. This rhythmic pattern of mRNA and protein expression was recapitulated in vitro in serum-shocked differentiated skeletal muscle cells. p21WAF1/CIP1 circadian expression is dramatically increased and no longer rhythmic in clock-deficient Bmal1-/- knock-out mice. Biochemical and genetic data show that oscillation of p21WAF1/CIP1 gene transcription is regulated by the antagonistic activities of the orphan nuclear receptors REV-ERBalpha/beta and RORalpha4/gamma, which are core clock regulators. Importantly, p21WAF1/CIP1 overexpressing Bmal1-/- primary hepatocytes exhibit a decreased proliferation rate. This phenotype could be reversed using small interfering RNA-mediated knockdown of p21WAF1/CIP1. These data establish a novel molecular link between clock and cell cycle genes and suggest that the G1 progression phase is a target of the circadian clock during liver cell proliferation.

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The Circadian Clock Component BMAL1 Is a Critical Regulator of p21 Expression and Hepatocyte Proliferation

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