Nucleocytoplasmic shuttling of the retinoblastoma tumor suppressor protein via Cdk phosphorylation-dependent nuclear export.
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.
Jiao
Wan
W
Cell Cycle and Human Diseases Group, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Datta
Jashodeep
J
Lin
Huei-Min
HM
Dundr
Miroslav
M
Rane
Sushil G
SG
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002460:Cell Line; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
D051358:Cyclin-Dependent Kinase 4; D017931:DNA Primers; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D000097606:Exportin 1 Protein; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse