Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells

Autor: Michael J. Spinella, Kelly C. Heim, Dexin Deng, Jason H. Moore, Craig R. Tomlinson, Sarah J. Freemantle, Kristina A. White
Rok vydání: 2007
Předmět:
Pluripotent Stem Cells
Cancer Research
Embryonal Carcinoma Stem Cells
Transcription
Genetic
Receptors
Retinoic Acid
Cellular differentiation
Retinoic acid
Tretinoin
Biology
lcsh:RC254-282
Embryonal carcinoma
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cancer stem cell
Differentiation therapy
Carcinoma
Embryonal
medicine
Humans
RNA
Small Interfering
Induced pluripotent stem cell
Adaptor Proteins
Signal Transducing
Oligonucleotide Array Sequence Analysis
030304 developmental biology
Feedback
Physiological
0303 health sciences
Research
Gene Expression Profiling
Nuclear Proteins
Cell Differentiation
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Neoplasm Proteins
Nuclear Receptor Interacting Protein 1
Gene Expression Regulation
Neoplastic
P19 cell
Oncology
chemistry
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Cancer research
Molecular Medicine
RNA Interference
Signal Transduction
Zdroj: Molecular Cancer, Vol 6, Iss 1, p 57 (2007)
Molecular Cancer
ISSN: 1476-4598
DOI: 10.1186/1476-4598-6-57
Popis: Background The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification of these genes would be of considerable interest. Results To begin to address this issue, microarray technology was employed to elucidate in a de novo fashion the global role of RIP140 in RA target gene regulation of embryonal carcinoma. Subclasses of genes were affected by RIP140 in distinct manners. Interestingly, approximately half of the RA-dependent genes were unaffected by RIP140. Hence, RIP140 appears to discriminate between different classes of RA target genes. In general, RIP140-dependent gene expression was consistent with RIP140 functioning to limit RA signaling and tumor cell differentiation. Few if any genes were regulated in a manner to support a role for RIP140 in "active repression". We also demonstrated that RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA. Conclusion Together the data demonstrates that RIP140 has profound effects on RA-mediated gene expression in this cancer stem cell model. The RIP140-dependent RA target genes identified here may be particularly important in mediating RA-induced tumor cell differentiation and the findings suggest that RIP140 may be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy. We discuss these data in the context of proposed models of RIP140-mediated repression.
Databáze: OpenAIRE
Externí odkaz: