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Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis

P P Joshi1, M V Kulkarni, B K Yu

  • 1Department of Biological Sciences, Purdue Cancer Center, Purdue University, West Lafayette, IN, USA.

Oncogene
|September 6, 2006
PubMed

Insights

Mutations in the RET proto-oncogene cause Multiple Endocrine Neoplasia type 2A (MEN2A). This study shows RET2A regulates both p18 and p27, key tumor suppressors, crucial for MEN2A development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Multiple Endocrine Neoplasia type 2A (MEN2A) is linked to RET proto-oncogene mutations.
  • Reduced p27(Kip1) expression is observed in thyroid tumors, with RET/PTC1 downregulating p27.
  • Loss of both p27 and p18(Ink4c) is critical for MEN tumor development, suggesting collaborative tumor suppression.

Purpose of the Study:

  • To investigate the role of the MEN2A-specific RET mutant, RET2A(C634R), in regulating cell cycle inhibitors p18 and p27.
  • To elucidate the mechanism by which RET2A influences p18 and p27 expression and its impact on cell proliferation.
  • To determine the in vivo relevance of these findings in MEN2A adrenal tumors.

Main Methods:

  • Utilized cell culture models expressing the RET2A(C634R) mutant.
  • Analyzed mRNA and protein levels of p18, p27, and cyclins D1/D2.
  • Assessed CDK activity, pRb phosphorylation, and cell proliferation.
  • Investigated the role of mitogen-activated protein kinase (MAPK) signaling.
  • Examined cell cycle gene expression in MEN2A adrenal tumors.

Main Results:

  • RET2A(C634R) induction led to decreased p18 and p27 levels, and increased cyclin D, CDK activity, pRb phosphorylation, and proliferation.
  • RET2A repressed p18/p27 mRNA and decreased p27 protein stability, while increasing cyclin D1 mRNA.
  • MAPK signaling was required for RET2A-mediated regulation of p18 and p27, but not cyclins D1/D2.
  • RET2A-dependent p18 repression was sufficient to drive cell proliferation.
  • MEN2A adrenal tumors exhibited similar cell cycle expression profiles.

Conclusions:

  • RET2A directly regulates p18 expression, in addition to p27.
  • The coordinated downregulation of p18 and p27 by RET2A is a key event in MEN2A tumorigenesis.
  • Targeting RET2A-mediated regulation of these CDKIs may offer therapeutic strategies for MEN2A.

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