Maeng, Sejung Kim, Gil Jung Choi, Eun Ju Yang, Hyun Ok Lee, Dong-Sup Sohn, Young Chang 2024-01-20T13:33:41Z 2024-01-20T13:33:41Z 2021-09-05 2012-11 0888-8809 https://pubs.kist.re.kr/handle/201004/128698 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 alpha (RXR alpha) 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 alpha as bait in a yeast two-hybrid screening. The interaction of RFC3 with RXR alpha 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 alpha. The transient interaction between 9-cis-RA-activated RXR alpha and RFC3 resulted in reconfiguration of the PCNA-RFC complex. Furthermore, we found that knockdown of RXR alpha 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 alpha suppresses the growth of RA-sensitive breast cancer and embryonic cells through RFC3. (Molecular Endocrinology 26: 1821-1835, 2012) English ENDOCRINE SOC NUCLEAR HORMONE-RECEPTORS DNA POLYMERASE-DELTA DEPENDENT TRANSACTIVATION SIGNALING PATHWAYS GENE-EXPRESSION CARCINOMA-CELLS RXR GENES IN-VITRO ANTIGEN APOPTOSIS 9-Cis-Retinoic Acid Induces Growth Inhibition in Retinoid-Sensitive Breast Cancer and Sea Urchin Embryonic Cells via Retinoid X Receptor alpha and Replication Factor C3 Article 10.1210/me.2012-1104 1 MOLECULAR ENDOCRINOLOGY, v.26, no.11, pp.1821 - 1835 MOLECULAR ENDOCRINOLOGY 26 11 1821 1835 scie scopus 000310584900004 2-s2.0-84868115581 Endocrinology & Metabolism Endocrinology & Metabolism Article NUCLEAR HORMONE-RECEPTORS DNA POLYMERASE-DELTA DEPENDENT TRANSACTIVATION SIGNALING PATHWAYS GENE-EXPRESSION CARCINOMA-CELLS RXR GENES IN-VITRO ANTIGEN APOPTOSIS NURSA Molecule Pages Nuclear Receptors RXR-α Ligands:9-cis-retinoic acid