p18Ink4c and p53 Act as tumor suppressors in cyclin D1-driven primitive neuroectodermal tumor.

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.

[1]  Hai Yan,et al.  Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme. , 2008, Cancer research.

[2]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.

[3]  D. Carrasco,et al.  Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. , 2007, Cancer research.

[4]  F. Zindy,et al.  Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors. , 2007, Cancer research.

[5]  K. Millen,et al.  Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation , 2006, Development.

[6]  D. Peeper,et al.  Oncogene-induced cell senescence--halting on the road to cancer. , 2006, The New England journal of medicine.

[7]  M. Hatten,et al.  The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. , 2005, Genes & development.

[8]  S. Skapek,et al.  The Arf Tumor Suppressor Regulates Platelet-Derived Growth Factor Receptor ? Signaling: A New View through the Eyes of Arf-/- Mice , 2005, Cell cycle.

[9]  F. Zindy,et al.  Arf‐dependent regulation of Pdgf signaling in perivascular cells in the developing mouse eye , 2005, The EMBO journal.

[10]  A. Papanikolaou,et al.  Cyclin D1 in breast cancer pathogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  D. Cobrinik Pocket proteins and cell cycle control , 2005, Oncogene.

[12]  J. Campisi Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors , 2005, Cell.

[13]  F. Kokocinski,et al.  Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. , 2004, Cancer research.

[14]  J. Shay,et al.  Hallmarks of senescence in carcinogenesis and cancer therapy , 2004, Oncogene.

[15]  R. Gilbertson,et al.  Medulloblastoma: signalling a change in treatment. , 2004, The Lancet. Oncology.

[16]  C. Sherr,et al.  Principles of Tumor Suppression , 2004, Cell.

[17]  F. Zindy,et al.  Hemangiosarcomas, medulloblastomas, and other tumors in Ink4c/p53-null mice. , 2003, Cancer research.

[18]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[19]  Robert J. Wechsler-Reya,et al.  Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Lowe,et al.  Oncogenic ras and p53 Cooperate To Induce Cellular Senescence , 2002, Molecular and Cellular Biology.

[21]  F. Zindy,et al.  The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Diehl Cycling to Cancer with Cyclin D1 , 2002, Cancer biology & therapy.

[23]  T. van Dyke,et al.  p19ARF Is Dispensable for Oncogenic Stress-Induced p53-Mediated Apoptosis and Tumor Suppression In Vivo , 2002, Molecular and Cellular Biology.

[24]  Thierry Soussi,et al.  Assessing TP53 status in human tumours to evaluate clinical outcome , 2001, Nature Reviews Cancer.

[25]  J. Campisi Cellular senescence as a tumor-suppressor mechanism. , 2001, Trends in cell biology.

[26]  E. Y. Lee,et al.  Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development , 2001, Oncogene.

[27]  Y. Shyr,et al.  Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice. , 2001, Cancer research.

[28]  P. Chan,et al.  Evaluation of extraction methods from paraffin wax embedded tissues for PCR amplification of human and viral DNA , 2001, Journal of clinical pathology.

[29]  D. Rowitch,et al.  Sonic hedgehog Promotes G1 Cyclin Expression and Sustained Cell Cycle Progression in Mammalian Neuronal Precursors , 2000, Molecular and Cellular Biology.

[30]  M. Barbacid,et al.  Limited overlapping roles of P15INK4b and P18INK4c cell cycle inhibitors in proliferation and tumorigenesis , 2000, The EMBO journal.

[31]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[32]  T. Kivelä,et al.  Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[34]  J. Harper,et al.  Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. , 1997, Molecular biology of the cell.

[35]  M. Kitagawa,et al.  The consensus motif for phosphorylation by cyclin D1‐Cdk4 is different from that for phosphorylation by cyclin A/E‐Cdk2. , 1996, The EMBO journal.

[36]  T. H. Newton,et al.  Development of the pineal gland: measurement with MR. , 1996, AJNR. American journal of neuroradiology.

[37]  J. Trojanowski,et al.  Animal Models of Medulloblastomas and Related Primitive Neuroectodermal Tumors. A Review , 1995, Journal of neuropathology and experimental neurology.

[38]  H. Lovec,et al.  Cyclin D1/bcl‐1 cooperates with myc genes in the generation of B‐cell lymphoma in transgenic mice. , 1994, The EMBO journal.

[39]  T. Jacks,et al.  Cooperative tumorigenic effects of germline mutations in Rb and p53 , 1994, Nature Genetics.

[40]  Emma Lees,et al.  Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice , 1994, Nature.

[41]  J.M. Adams,et al.  Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. , 1994, The EMBO journal.

[42]  A. Levine,et al.  Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. , 1994, Cancer research.

[43]  R. Weinberg,et al.  Regulation of retinoblastoma protein functions by ectopic expression of human cyclins , 1992, Cell.

[44]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[45]  M. Al-Ubaidi,et al.  Tissue-specific expression in transgenic mice directed by the 5'-flanking sequences of the human gene encoding interphotoreceptor retinoid-binding protein. , 1990, The Journal of biological chemistry.

[46]  L. Becker,et al.  Primitive neuroectodermal tumors of the central nervous system. , 1983, Human pathology.

[47]  D. Abramson,et al.  Trilateral retinoblastoma--incidence and outcome: a decade of experience. , 1994, International journal of radiation oncology, biology, physics.