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 approximately 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.