RIalpha influences cellular proliferation in cancer cells by transporting RFC40 into the nucleus.
The regulatory subunit (RIalpha) of cAMP-dependent Protein Kinase A (PKA) is overexpressed in a variety of tumors and carcinomas such as renal cell carcinomas, pituitary tumors of the rat, malignant osteoblasts, colon carcinomas, serous ovarian tumors and primary human breast carcinomas. However, the direct relation between overexpression of RIalpha and malignancy is still unclear. We have recently identified a novel interaction between RIalpha and RFC40, the second subunit of Replication Factor C (RFC), and have demonstrated that this interaction may be associated with cell survival. Coincidentally, RFC40 is overexpressed in gestational trophoblastic diseases such as choriocarcinomas. This study was undertaken to investigate a possible functional role for both these proteins together, in DNA replication and cellular proliferation. In the course of this study, a nonconventional nuclear localization signal was identified for RIalpha. Nuclear transport of RFC40 was found to be dependent on RIalpha, and this transport appeared to be a crucial step for cell cycle progression from G1 to S phase. Impairment in the nuclear transport of RFC40 by RIalpha arrested cells in G1 phase. These findings provide evidence for a previously unknown mechanism for the nuclear transport of RFC40 and also for a novel mechanism for cellular proliferation.
Gupte
Rakhee S
RS
Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.
Pozarowski
Piotr
P
Grabarek
Jerzy
J
Traganos
Frank
F
Darzynkiewicz
Zbigniew
Z
Lee
Marietta Y W T
MY
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000595:Amino Acid Sequence; D001692:Biological Transport / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D016193:G1 Phase; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000737:chemistry; D051818:Replication Protein C / Q000378:metabolism*; D016196:S Phase; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D019913:Nuclear Localization Signals; C517834:PRKAR1A protein, human; C517836:Prkar1a protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D051818:Replication Protein C