title: p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation.
abstract: 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 p19(Ink4d) (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.
authors.affiliation: Molecular Oncology Program, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: Molecular Oncology Program, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Ho Lam
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
authors.affiliation: Molecular Oncology Program, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA xhpei@med.miami.edu.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
mesh_terms: D000818:Animals; D001835:Body Weight; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000172:deficiency / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D004622:Embryo, Mammalian / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D056426:Genetic Loci; D007247:Infertility, Female / Q000473:pathology; D007248:Infertility, Male / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology; D008184:Luteal Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010903:Pituitary Gland, Anterior / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D025521:Tumor Suppressor Proteins; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6