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Glycogen synthase kinase 3beta phosphorylates p21WAF1/CIP1 for proteasomal degradation after UV irradiation

Ji Young Lee1, Su Jin Yu, Yun Gyu Park

  • 1Korea University College of Medicine, 126-1 Anam-Dong 5-Ga, Sungbuk-Gu, Seoul 136-705, South Korea. biojs@korea.ac.kr.

Molecular and Cellular Biology
|February 7, 2007
PubMed

Insights

UV radiation triggers the degradation of p21 protein via the proteasome. Glycogen synthase kinase 3 beta (GSK-3beta) phosphorylates p21, mediating this UV-induced degradation through the ATR signaling pathway.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Biochemistry

Background:

  • UV irradiation is known to induce p21 protein degradation.
  • The precise biochemical mechanism linking UV exposure to p21 degradation remains unclear.
  • Understanding this pathway is crucial for comprehending cellular responses to DNA damage.

Purpose of the Study:

  • To elucidate the biochemical mechanism of UV-induced p21 protein degradation.
  • To identify the specific kinases involved in p21 destabilization post-UV exposure.
  • To explore the role of the ATR signaling pathway in regulating p21 stability.

Main Methods:

  • Investigated the phosphorylation of p21 at serine 114 (ser-114) using GSK-3beta.
  • Utilized UV irradiation, caffeine treatment, and ATR small interfering RNA (siRNA) to study signaling pathways.
  • Employed proteasome inhibitors and a nonphosphorylatable S114A mutant of p21 to assess degradation mechanisms.
  • Examined the role of ubiquitination in p21 degradation.

Main Results:

  • UV irradiation activates GSK-3beta in an ATR-dependent manner.
  • GSK-3beta phosphorylates p21 at ser-114, which is essential for its UV-induced degradation.
  • The S114A mutant of p21 is resistant to UV-induced destabilization.
  • p21 degradation occurs via the proteasome and is independent of p53 status and ubiquitination.

Conclusions:

  • GSK-3beta acts as a critical mediator between UV-induced ATR activation and p21 degradation.
  • Phosphorylation of p21 at ser-114 by GSK-3beta is a key step in its proteasomal degradation following UV exposure.
  • This study reveals a novel mechanism for regulating p21 stability in response to DNA damage.

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