Distinct mechanisms for regulating the tumor suppressor and antiapoptotic functions of Rb

Duanduan Ma, Ping Zhou, J. William Harbour

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

The retinoblastoma protein, Rb, suppresses tumorigenesis by inhibiting cell proliferation and promoting senescence and differentiation. Paradoxically, Rb also inhibits apoptosis, which would seem to oppose its tumor suppressor function. Further, most human cancer cells inactivate Rb by hyperphosphorylation and demonstrate increased proliferative capacity but not high levels of apoptosis. As a potential explanation for these findings, we show here that the tumor suppressor and antiapoptotic functions of Rb are regulated by distinct phosphorylation events. Phosphorylation of sites in the C terminus occurs efficiently every cell cycle and regulates proliferation. Phosphorylation of Ser567 is inefficient and does not occur during the normal cell cycle. However, high cyclin-dependent kinase activity promotes phosphorylation of Ser567 by inducing an intramolecular interaction that leads to release of E2F, degradation of Rb, and susceptibility to apoptosis. Thus, phosphorylation of Ser567 may limit excessive proliferation by triggering cell death under hyperproliferative conditions. These findings suggest that the antiproliferative and antiapoptotic activities of Rb may represent complementary functions that work in concert to maintain the proliferation rate of cells within certain limits. As a survival strategy, some cancer cells may exploit this dual role of Rb by phosphorylating sites that regulate tumor suppression but avoiding phosphorylation of Ser567 and consequent apoptotic stimulus.

Original languageEnglish
Pages (from-to)19358-19366
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number21
DOIs
StatePublished - May 23 2003
Externally publishedYes

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Phosphorylation
Tumors
Cells
Neoplasms
Apoptosis
Cell Cycle
Cell Proliferation
Retinoblastoma Protein
Cyclin-Dependent Kinases
Cell proliferation
Cell death
Carcinogenesis
Cell Death
Degradation
Survival

ASJC Scopus subject areas

  • Biochemistry

Cite this

Distinct mechanisms for regulating the tumor suppressor and antiapoptotic functions of Rb. / Ma, Duanduan; Zhou, Ping; William Harbour, J.

In: Journal of Biological Chemistry, Vol. 278, No. 21, 23.05.2003, p. 19358-19366.

Research output: Contribution to journalArticle

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