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J. Biol. Chem., Vol. 279, Issue 49, 51100-51106, December 3, 2004

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Cdk4 Is Indispensable for Postnatal Proliferation of the Anterior Pituitary^*

Siwanon Jirawatnotai, Aileen Aziyu, Evan C. Osmundson, David S. Moons, Xianghong Zou, Rhonda D. Kineman, and Hiroaki Kiyokawa¶

From the Departments of Biochemistry and Molecular Genetics and Medicine, University of Illinois College of Medicine, Chicago, Illinois 60607

For proper development and tissue homeostasis, cell cycle progression is controlled by multilayered mechanisms. Recent studies using knock-out mice have shown that animals can develop relatively normally with deficiency for each of the G₁/S-regulatory proteins, D-type and E-type cyclins, cyclin-dependent kinase 4 (Cdk4), and Cdk2. Although Cdk4-null mice show no embryonic lethality, they exhibit specific endocrine phenotypes, i.e. dwarfism, infertility, and diabetes. Here we have demonstrated that Cdk4 plays an essential non-redundant role in postnatal proliferation of the anterior pituitary. Pituitaries from wild-type and Cdk4-null embryos at embryonic day 17.5 are morphologically indistinguishable with similar numbers of cells expressing a proliferating marker, Ki67, and cells expressing a differentiation marker, growth hormone. In contrast, anterior pituitaries of Cdk4-null mice at postnatal 8 weeks are extremely hypoplastic with markedly decreased numbers of Ki67⁺ cells, suggesting impaired cell proliferation. Pituitary hyperplasia induced by transgenic expression of human growth hormone-releasing hormone (GHRH) is significantly diminished in the Cdk4+/– genetic background and completely abrogated in the Cdk4–/– background. Small interfering RNA (siRNA)-mediated knockdown of Cdk4 inhibits GHRH-induced proliferation of GH3 somato/lactotroph cells with restored expression of GHRH receptors. Cdk4 siRNA also inhibits estrogen-dependent cell proliferation in GH3 cells and closely related GH4 cells. In contrast, Cdk6 siRNA does not diminish proliferation of these cells. Furthermore, Cdk4 siRNA does not affect GHRH-induced proliferation of mouse embryonic fibroblasts or estrogen-dependent proliferation of mammary carcinoma MCF-7 cells. Taken together, Cdk4 is dispensable for prenatal development of the pituitary or proliferation of other non-endocrine tissues but indispensable specifically for postnatal proliferation of somato/lactotrophs.

Received for publication, August 9, 2004 , and in revised form, September 20, 2004.

^* This work was supported by National Institutes of Health Grants HD38085 and CA100204 (to H. K.) and by the National Institutes of Health-sponsored Center for Women's Health and Reproduction (U54 HD40093). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, 900 S. Ashland Ave., M/C 669, Chicago, IL 60607-7170. Tel.: 312-355-1601; Fax: 312-413-2028; E-mail: kiyokawa{at}uic.edu.

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