p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors

Feng Bai, Xin-Hai Pei, Toru Nishikawa, Matthew D. Smith, Yue Xiong

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18 Ink4c and p27Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18-/- Men1 +/- mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18-/- and Men1 +/- cells and was further increased in p18-/-; Men1 +/- cells. The remaining wild-type Men1 allele was lost in most tumors from Men1+/- mice but was retained in most tumors from p18-/-; Men1+/- mice. Combined mutations of p27 -/- and Men1+/-, in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that menin may regulate additional factor(s) that interact with p18 and p27 differently.

Original languageEnglish
Pages (from-to)1495-1504
Number of pages10
JournalMolecular and Cellular Biology
Volume27
Issue number4
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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Neuroendocrine Tumors
Neoplasms
Cyclin-Dependent Kinase Inhibitor p18
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 1
Retinoblastoma Protein
Retinoblastoma
Tumor Suppressor Genes
Islets of Langerhans
Pancreas
Thyroid Gland
Phosphotransferases
Alleles
Phosphorylation
Cell Proliferation
Mutation
Incidence
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. / Bai, Feng; Pei, Xin-Hai; Nishikawa, Toru; Smith, Matthew D.; Xiong, Yue.

In: Molecular and Cellular Biology, Vol. 27, No. 4, 01.02.2007, p. 1495-1504.

Research output: Contribution to journalArticle

Bai, Feng ; Pei, Xin-Hai ; Nishikawa, Toru ; Smith, Matthew D. ; Xiong, Yue. / p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 4. pp. 1495-1504.
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