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MEN1 tumorigenesis in the pituitary and pancreatic islet requires CDK4 but not Cdk2

Gillam, M. P. ; Nimbalkar, D. ; Sun, L. ; Christov, K. ; Ray, D. ; Kaldis, P. LU orcid ; Liu, X. and Kiyokawa, H. (2015) In Oncogene 34(7). p.932-938
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... (More)

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, Men+/-; 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.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Cell cycle, Insulinoma, Knockout mice, Menin, Pituitary
in
Oncogene
volume
34
issue
7
pages
932 - 938
publisher
Nature Publishing Group
external identifiers
  • pmid:24531709
  • scopus:84938489166
ISSN
0950-9232
DOI
10.1038/onc.2014.3
language
English
LU publication?
no
id
33ca12a1-a256-4e0c-8b1d-5d668f64a16d
date added to LUP
2019-09-18 13:51:36
date last changed
2024-04-16 20:32:37
@article{33ca12a1-a256-4e0c-8b1d-5d668f64a16d,
  abstract     = {{<p>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<sup>-/-</sup> mice) exhibit hypoplasia in the pituitary and pancreatic islet due to primary postnatal defects in proliferation. Intriguingly, those neuroendocrine tissues affected in Cdk4<sup>-/-</sup> 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<sup>+/-</sup>) 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<sup>+/-</sup> mice. A majority of Men1<sup>+/-</sup> mice with wild-type CDKs developed pituitary and islet tumors by 15 months of age. Strikingly, Men1<sup>+/-</sup>; Cdk4<sup>-/-</sup> mice did not develop any tumors, and their islets and pituitaries remained hypoplastic with decreased proliferation. In contrast, Men<sup>+/-</sup>; Cdk2<sup>-/-</sup> mice showed pituitary and islet tumorigenesis comparable to those in Men1<sup>+/-</sup> mice. Pituitaries of Men1<sup>+/-</sup>; Cdk4<sup>-/-</sup> mice showed no signs of loss of heterozygosity (LOH) in the Men1 locus, whereas tumors in Men1<sup>+/-</sup> mice and Men1<sup>+/-</sup>; Cdk2<sup>-/-</sup> 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.</p>}},
  author       = {{Gillam, M. P. and Nimbalkar, D. and Sun, L. and Christov, K. and Ray, D. and Kaldis, P. and Liu, X. and Kiyokawa, H.}},
  issn         = {{0950-9232}},
  keywords     = {{Cell cycle; Insulinoma; Knockout mice; Menin; Pituitary}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{932--938}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Oncogene}},
  title        = {{MEN1 tumorigenesis in the pituitary and pancreatic islet requires CDK4 but not Cdk2}},
  url          = {{http://dx.doi.org/10.1038/onc.2014.3}},
  doi          = {{10.1038/onc.2014.3}},
  volume       = {{34}},
  year         = {{2015}},
}