p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation

Feng Bai, Ho Lam Chan, Matthew D. Smith, Hiroaki Kiyokawa, Xin Hai Pei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Pituitary tumors develop in about one-quarter of the population, and most arise from the anterior lobe (AL). The pituitary gland is particularly sensitive to genetic alteration of genes involved in the cyclin-dependent kinase (CDK) inhibitor (CKI)-CDK-retinoblastoma protein (Rb) pathway. Mice heterozygous for the Rb mutation develop pituitary tumors, with about 20% arising from the AL. Perplexingly, none of the CKI-deficient mice reported thus far develop pituitary AL tumors. In this study, we show that deletion of p19Ink4d (p19), a CKI gene, in mice results in spontaneous development of tumors in multiple organs and tissues. Specifically, more than one-half of the mutant mice developed pituitary hyperplasia or tumors predominantly in the AL. Tumor development is associated with increased cell proliferation and enhanced activity of Cdk4 and Cdk6 and phosphorylation of Rb protein. Though Cdk4 is indispensable for postnatal pituitary cell proliferation, it is not required for the hyperproliferative pituitary phenotype caused by p19 loss. Loss of p19 phosphorylates Rb in Cdk4-/-pituitary AL cells and mouse embryonic fibroblasts (MEFs) and rescues their proliferation defects, at least partially, through the activation of Cdk6. These results provide the first genetic evidence that p19 is a tumor suppressor and the major CKI gene that controls pituitary AL cell proliferation.

Original languageEnglish (US)
Pages (from-to)2121-2134
Number of pages14
JournalMolecular and cellular biology
Issue number12
StatePublished - Jun 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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