GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy

Cell Signal. 2008 Apr;20(4):581-9. doi: 10.1016/j.cellsig.2007.10.018. Epub 2007 Oct 23.

Abstract

Cyclin D1 is known as a proto-oncogene whose gene amplification and protein overexpression are frequently observed in tumor cells. It acts as a mitogenic signal sensor and is expressed as a delayed-early response to many mitogenic signals. Cyclin-dependent kinases (CDKs) 4 and 6 are cyclin D1 binding partners, and activated cyclin D1/CDK4 and cyclin D1/CDK6 complex phosphorylate the retinoblastoma protein to induce the expression of target genes essential for S phase entry, resulting in facilitation of the progression from G1 to S phase. As well as acting as a positive regulator of the cell cycle, cyclin D1 is known to bind and modulate the actions of several transcription factors. Since the protein level of cyclin D1 reflects cell cycle progression, the rates of protein production and degradation are strictly regulated. Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been shown to play an important role in the determination of cyclin D1 expression level by regulating mRNA transcription and protein degradation. This review highlights the regulatory mechanisms of cyclin D1 expression level, with special attention to the involvement of GSK-3beta.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Celecoxib
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Curcumin / pharmacology
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Enzyme Activation
  • Enzyme Activators / pharmacology*
  • Enzyme Activators / therapeutic use
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Processing, Post-Translational / drug effects*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / pharmacology
  • Retinoids / pharmacology
  • Signal Transduction / drug effects*
  • Sulfonamides / pharmacology
  • Transcription, Genetic / drug effects
  • Ubiquitins / metabolism
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Activators
  • Pyrazoles
  • Retinoids
  • Sulfonamides
  • Ubiquitins
  • Wnt Proteins
  • beta Catenin
  • Cyclin D1
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein-Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3
  • Curcumin
  • Celecoxib