This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saab, R. Articles by Skapek, S. X. Search for Related Content PubMed PubMed Citation Articles by Saab, R. Articles by Skapek, S. X.

p18^Ink4c and p53 Act as Tumor Suppressors in Cyclin D1–Driven Primitive Neuroectodermal Tumor

¹ Children's Cancer Center of Lebanon, American University of Beirut Medical Center, Beirut, Lebanon; Departments of ² Oncology, ³ Radiological Sciences, ⁴ Pathology, and ⁵ Biostatistics and ⁶ Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee; and ⁷ Department of Pediatrics, Section of Hematology-Oncology, University of Chicago, Chicago, Illinois

Requests for reprints: Raya Saab, Pediatric Hematology/Oncology, American University of Beirut, Riad El Solh, Beirut 1107 2020, Lebanon. Phone: 961-3-174402; Fax: 961-1-366384; E-mail: rs88{at}aub.edu.lb or Stephen X. Skapek, Pediatric Hematology/Oncology MC4060, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail: sskapek{at}peds.bsd.uchicago.edu.

Key Words: Cyclin D1 • p53 • Ink4c • PNET • brain

The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to 4 months. Interestingly, the Cdk inhibitor p18^Ink4c was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18^Ink4c is a tumor suppressor in cyclin D1–driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption. [Cancer Res 2009;69(2):440–8]