9-Cis-retinoic acid induces growth inhibition in retinoid-sensitive breast cancer and sea urchin embryonic cells via retinoid X receptor ? and replication factor C3.

ABSTRACT: There is widespread interest in defining factors and mechanisms that suppress the proliferation of cancer cells. Retinoic acid (RA) is a potent suppressor of mammary cancer and developmental embryonic cell proliferation. However, the molecular mechanisms by which 9-cis-RA signaling induces growth inhibition in RA-sensitive breast cancer and embryonic cells are not apparent. Here, we provide evidence that the inhibitory effect of 9-cis-RA on cell proliferation depends on 9-cis-RA-dependent interaction of retinoid X receptor ? (RXR?) with replication factor C3 (RFC3), which is a subunit of the RFC heteropentamer that opens and closes the circular proliferating cell nuclear antigen (PCNA) clamp on DNA. An RFC3 ortholog in a sea urchin cDNA library was isolated by using the ligand-binding domain of RXR? as bait in a yeast two-hybrid screening. The interaction of RFC3 with RXR? depends on 9-cis-RA and bexarotene, but not on all-trans-RA or an RA receptor (RAR)-selective ligand. Truncation and mutagenesis experiments demonstrated that the C-terminal LXXLL motifs in both human and sea urchin RFC3 are critical for the interaction with RXR?. The transient interaction between 9-cis-RA-activated RXR? and RFC3 resulted in reconfiguration of the PCNA-RFC complex. Furthermore, we found that knockdown of RXR? or overexpression of RFC3 impairs the ability of 9-cis-RA to inhibit proliferation of MCF-7 breast cancer cells and sea urchin embryogenesis. Our results indicate that 9-cis-RA-activated RXR? suppresses the growth of RA-sensitive breast cancer and embryonic cells through RFC3.

SUBMITTER: Maeng S 

PROVIDER: S-EPMC5416959 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature