Tumor promotion by caspase-resistant retinoblastoma protein

Helena L. Borges, Jeff Bird, Katherine Wasson, Robert Cardiff, Nissi Varki, Lars Eckmann, Jean Y.J. Wang

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The retinoblastoma (RB) protein regulates cell proliferation and cell death. RB is cleaved by caspase during apoptosis. A mutation of the caspase-cleavage site in the RB C terminus has been made in the mouse Rb-1 locus; the resulting Rb-MI mice are resistant to endotoxin-induced apoptosis in the intestine. The Rb-MI mice do not exhibit increased tumor incidence, because the MI mutation does not disrupt the Rb tumor suppressor function. In this study, we show that Rb-MI can promote the formation of colonic adenomas in the p53-null genetic background. Consistent with this tumor phenotype, Rb-MI reduces colorectal epithelial apoptosis and ulceration caused by dextran sulfate sodium. By contrast, Rb-MI does not affect the lymphoma phenotype of p53-null mice, in keeping with its inability to protect thymocytes and splenocytes from apoptosis. The Rb-MI protein is expressed and phosphorylated in the tumors, thereby inactivating its growth suppression function. These results suggest that RB tumor suppressor function, i.e., inhibition of proliferation, is inactivated by phosphorylation, whereas RB tumor promoting function, i.e., inhibition of apoptosis, is inactivated by caspase cleavage.

Original languageEnglish (US)
Pages (from-to)15587-15592
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number43
DOIs
StatePublished - Oct 25 2005

Fingerprint

Retinoblastoma Protein
Caspases
Retinoblastoma
Apoptosis
Neoplasms
Phenotype
Dextran Sulfate
Mutation
Thymocytes
Endotoxins
Adenoma
Intestines
Lymphoma
Cell Death
Phosphorylation
Cell Proliferation
Incidence
Growth

Keywords

  • Apoptosis
  • Dextran sulfate sodium
  • p53-knockout
  • Tumor promoter
  • Tumor suppressor

ASJC Scopus subject areas

  • General

Cite this

Tumor promotion by caspase-resistant retinoblastoma protein. / Borges, Helena L.; Bird, Jeff; Wasson, Katherine; Cardiff, Robert; Varki, Nissi; Eckmann, Lars; Wang, Jean Y.J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 43, 25.10.2005, p. 15587-15592.

Research output: Contribution to journalArticle

Borges, Helena L. ; Bird, Jeff ; Wasson, Katherine ; Cardiff, Robert ; Varki, Nissi ; Eckmann, Lars ; Wang, Jean Y.J. / Tumor promotion by caspase-resistant retinoblastoma protein. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 43. pp. 15587-15592.
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AU - Borges, Helena L.

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AU - Wasson, Katherine

AU - Cardiff, Robert

AU - Varki, Nissi

AU - Eckmann, Lars

AU - Wang, Jean Y.J.

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