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

Authors
Maeng, SejungKim, Gil JungChoi, Eun JuYang, Hyun OkLee, Dong-SupSohn, Young Chang
Issue Date
2012-11
Publisher
ENDOCRINE SOC
Citation
MOLECULAR ENDOCRINOLOGY, v.26, no.11, pp.1821 - 1835
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 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)
Keywords
NUCLEAR HORMONE-RECEPTORS; DNA POLYMERASE-DELTA; DEPENDENT TRANSACTIVATION; SIGNALING PATHWAYS; GENE-EXPRESSION; CARCINOMA-CELLS; RXR GENES; IN-VITRO; ANTIGEN; APOPTOSIS; 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
ISSN
0888-8809
URI
https://pubs.kist.re.kr/handle/201004/128698
DOI
10.1210/me.2012-1104
Appears in Collections:
KIST Article > 2012
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