title: 9-Cis-retinoic acid induces growth inhibition in retinoid-sensitive breast cancer and sea urchin embryonic cells via retinoid X receptor α 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 α (RXRα) 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 RXRα as bait in a yeast two-hybrid screening. The interaction of RFC3 with RXRα 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 RXRα. The transient interaction between 9-cis-RA-activated RXRα and RFC3 resulted in reconfiguration of the PCNA-RFC complex. Furthermore, we found that knockdown of RXRα 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 RXRα suppresses the growth of RA-sensitive breast cancer and embryonic cells through RFC3.
authors.affiliation: Department of Marine Molecular Biotechnology, College of Life Sciences, Gangneung-Wonju National University, Gangneung 210-702, Republic of Korea.
authors.forename: Sejung
authors.initials: S
authors.lastname: Maeng
authors.forename: Gil Jung
authors.initials: GJ
authors.lastname: Kim
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Hyun Ok
authors.initials: HO
authors.lastname: Yang
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.forename: Young Chang
authors.initials: YC
authors.lastname: Sohn
mesh_terms: D000077556:Alitretinoin; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian / Q000166:cytology*; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008024:Ligands; D008845:Microinjections; D008954:Models, Biological; D008969:Molecular Sequence Data; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D051818:Replication Protein C / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D012617:Sea Urchins / Q000187:drug effects / Q000196:embryology* / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D008024:Ligands; D018809:Proliferating Cell Nuclear Antigen; D047490:Retinoid X Receptor alpha; D012176:Retinoids; D000077556:Alitretinoin; D014212:Tretinoin; D051818:Replication Protein C