title: MEN1 tumorigenesis in the pituitary and pancreatic islet requires Cdk4 but not Cdk2.
abstract: Recent studies suggest that physiological and tumorigenic proliferation of mammalian cells is controlled by multiple cyclin-dependent kinases (CDKs) largely in tissue-specific manners. We and others previously demonstrated that adult mice deficient for the Cyclin D partner CDK4 (Cdk4(-/-) mice) exhibit hypoplasia in the pituitary and pancreatic islet due to primary postnatal defects in proliferation. Intriguingly, those neuroendocrine tissues affected in Cdk4(-/-) mice are the primary targets of tumorigenesis in the syndrome of multiple endocrine neoplasia type-1 (MEN1). Mice with heterozygous disruption of the tumor suppressor Men1 gene (Men1(+/-)) develop tumors in the pituitary, pancreatic islets and other neuroendocrine tissues, which is analogous to humans with MEN1 mutations. To explore the genetic interactions between loss of Men1 and activation of CDKs, we examined the impact of Cdk4 or Cdk2 disruption on tumorigenesis in Men1(+/-) mice. A majority of Men1(+/-) mice with wild-type CDKs developed pituitary and islet tumors by 15 months of age. Strikingly, Men1(+/-); Cdk4(-/-) mice did not develop any tumors, and their islets and pituitaries remained hypoplastic with decreased proliferation. In contrast, Men1(+/-); Cdk2(-/-) mice showed pituitary and islet tumorigenesis comparable to those in Men1(+/-) mice. Pituitaries of Men1(+/-); Cdk4(-/-) mice showed no signs of loss of heterozygosity (LOH) in the Men1 locus, whereas tumors in Men1(+/-) mice and Men1(+/-); Cdk2(-/-) mice exhibited LOH. Consistently, CDK4 knockdown in INS-1 insulinoma cells inhibited glucose-stimulated cell cycle progression with a significant decrease in phosphorylation of retinoblastoma protein (RB) at specific sites including Ser780. CDK2 knockdown had minimum effects on RB phosphorylation and cell cycle progression. These data suggest that CDK4 is a critical downstream target of MEN1-dependent tumor suppression and is required for tumorigenic proliferation in the pituitary and pancreatic islet, whereas CDK2 is dispensable for tumorigenesis in these neuroendocrine cell types.
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: M P
authors: MP
authors: Gillam
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: D
authors: D
authors: Nimbalkar
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: L
authors: L
authors: Sun
authors: Department of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
authors: K
authors: K
authors: Christov
authors: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: D
authors: D
authors: Ray
authors: 1] Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Republic of Singapore [2] Department of Biochemistry, National University of Singapore (NUS), Singapore, Republic of Singapore.
authors: P
authors: P
authors: Kaldis
authors: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: X
authors: X
authors: Liu
authors: 1] Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA [2] Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: H
authors: H
authors: Kiyokawa
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C484898:Men1 protein, mouse; C532041:Men1 protein, rat; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; C495902:Cdk4 protein, mouse; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4