p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor

Raya Saab, Carlos Rodriguez-Galindo, Kelly Matmati, Jerold E. Rehg, Shannon H. Baumer, Joseph D. Khoury, Catherine Billups, Geoffrey Neale, Kathleen J. Helton, Stephen X. Skapek

Research output: Contribution to journalArticle

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Abstract

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 p18Ink4c 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 p18Ink4c 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.

Original languageEnglish (US)
Pages (from-to)440-448
Number of pages9
JournalCancer Research
Volume69
Issue number2
DOIs
StatePublished - Jan 15 2009

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Primitive Neuroectodermal Tumors
Cyclin D1
Retinoblastoma
Pineal Gland
Neoplasms
Transgenic Mice
Brain
Cyclin-Dependent Kinase 4
Retinoblastoma Protein
Medulloblastoma
Heterochromatin
Cyclin-Dependent Kinases
Chemoprevention
Transgenes
Cerebellum
Phosphorylation
Cell Proliferation
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Saab, R., Rodriguez-Galindo, C., Matmati, K., Rehg, J. E., Baumer, S. H., Khoury, J. D., ... Skapek, S. X. (2009). p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor. Cancer Research, 69(2), 440-448. https://doi.org/10.1158/0008-5472.CAN-08-1892

p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor. / Saab, Raya; Rodriguez-Galindo, Carlos; Matmati, Kelly; Rehg, Jerold E.; Baumer, Shannon H.; Khoury, Joseph D.; Billups, Catherine; Neale, Geoffrey; Helton, Kathleen J.; Skapek, Stephen X.

In: Cancer Research, Vol. 69, No. 2, 15.01.2009, p. 440-448.

Research output: Contribution to journalArticle

Saab, R, Rodriguez-Galindo, C, Matmati, K, Rehg, JE, Baumer, SH, Khoury, JD, Billups, C, Neale, G, Helton, KJ & Skapek, SX 2009, 'p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor', Cancer Research, vol. 69, no. 2, pp. 440-448. https://doi.org/10.1158/0008-5472.CAN-08-1892
Saab R, Rodriguez-Galindo C, Matmati K, Rehg JE, Baumer SH, Khoury JD et al. p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor. Cancer Research. 2009 Jan 15;69(2):440-448. https://doi.org/10.1158/0008-5472.CAN-08-1892
Saab, Raya ; Rodriguez-Galindo, Carlos ; Matmati, Kelly ; Rehg, Jerold E. ; Baumer, Shannon H. ; Khoury, Joseph D. ; Billups, Catherine ; Neale, Geoffrey ; Helton, Kathleen J. ; Skapek, Stephen X. / p18Ink4c and p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor. In: Cancer Research. 2009 ; Vol. 69, No. 2. pp. 440-448.
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abstract = "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 p18Ink4c 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 p18Ink4c 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.",
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AU - Baumer, Shannon H.

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