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MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2

M P Gillam1, D Nimbalkar1, L Sun1

  • 1Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Oncogene
|February 18, 2014
PubMed

Insights

Cyclin-dependent kinase 4 (CDK4) is essential for tumor development in the pituitary and pancreatic islet in mice with a disrupted Men1 gene. CDK4 acts as a critical downstream target for MEN1 tumor suppression, unlike CDK2.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammalian cell proliferation, including tumorigenic growth, is regulated by multiple cyclin-dependent kinases (CDKs) in a tissue-specific manner.
  • Mice lacking CDK4 (Cdk4(-/-)) exhibit hypoplasia in the pituitary and pancreatic islet, tissues targeted in Multiple Endocrine Neoplasia type 1 (MEN1).
  • Men1(+/-) mice, analogous to human MEN1 mutations, develop tumors in these neuroendocrine tissues.

Purpose of the Study:

  • To investigate the genetic interactions between Men1 loss and CDK activation in tumorigenesis.
  • To determine the specific roles of CDK4 and CDK2 in the development of pituitary and pancreatic islet tumors in Men1(+/-) mice.

Main Methods:

  • Examined the impact of Cdk4 or Cdk2 disruption on tumorigenesis in Men1(+/-) mice.
  • Analyzed tumor development, proliferation, and loss of heterozygosity (LOH) at the Men1 locus.
  • Utilized CDK4 and CDK2 knockdown in INS-1 insulinoma cells to assess effects on cell cycle progression and retinoblastoma protein (RB) phosphorylation.

Main Results:

  • Men1(+/-); Cdk4(-/-) mice showed no tumor development; pituitaries and islets remained hypoplastic with reduced proliferation.
  • Men1(+/-); Cdk2(-/-) mice exhibited tumorigenesis comparable to Men1(+/-) mice.
  • CDK4 knockdown significantly inhibited cell cycle progression and RB phosphorylation, while CDK2 knockdown had minimal effects.

Conclusions:

  • CDK4 is a critical downstream target of MEN1-dependent tumor suppression.
  • CDK4 is required for tumorigenic proliferation in the pituitary and pancreatic islet.
  • CDK2 is dispensable for tumorigenesis in these specific neuroendocrine cell types.

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