Nucleocytoplasmic shuttling of the retinoblastoma tumor suppressor protein via Cdk phosphorylation-dependent nuclear export

Wan Jiao, Jashodeep Datta, Huei Min Lin, Miroslav Dundr, Sushil G. Rane

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The retinoblastoma (RB) tumor suppressor protein is a negative regulator of cell proliferation that is functionally inactivated in the majority of human tumors. Elevated Cdk activity via RB pathway mutations is observed in virtually every human cancer. Thus, Cdk inhibitors have tremendous promise as anticancer agents although detailed mechanistic knowledge of their effects on RB function is needed to harness their full potential. Here, we illustrate a novel function for Cdks in regulating the subcellular localization of RB. We present evidence of significant cytoplasmic mislocalization of ordinarily nuclear RB in cells harboring Cdk4 mutations. Our findings uncover a novel mechanism to circumvent RB-mediated growth suppression by altered nucleocytoplasmic trafficking via the Exportin1 pathway. Cytoplasmically mislocalized RB could be efficiently confined to the nucleus by inhibiting the Exportin1 pathway, reducing Cdk activity, or mutating the Cdk-dependent phosphorylation sites in RB that result in loss of RB-Exportin1 association. Thus RB-mediated tumor suppression can be subverted by phosphorylation-dependent enhancement of nuclear export. These results support the notion that tumor cells can modulate the protein transport machinery thereby making the protein transport process a viable therapeutic target.

Original languageEnglish (US)
Pages (from-to)38098-38108
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number49
DOIs
StatePublished - Dec 8 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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