Identification and characterization of retinoic acid receptor beta2 target genes in F9 teratocarcinoma cells.
Retinoids, a group of natural and synthetic analogues of vitamin A (retinol), modulate the differentiation of many cell types. Retinoids are also used for the prevention and treatment of cancer. The actions of retinoids are generally mediated by the retinoic acid receptors (RARs alpha, beta, and gamma) and the retinoid X receptors (RXRs alpha, beta, and gamma). One of the RARs, RARbeta, is expressed at reduced levels in many human carcinomas, and F9 RARbeta(2)(-/-) cells do not growth arrest in response to RA. To determine if RARbeta(2) regulates the expression of a unique set of genes, through the use of subtractive hybridization and DNA array analysis, we have identified and characterized genes that are differentially expressed in F9 RARbeta(2)(-/-) teratocarcinoma cells. These genes, which encode transcription factors, cell surface signal transduction molecules, and metabolic enzymes, include c-myc, FOG1, GATA6, glutamate dehydrogenase, glutathione S-transferase homologue (p28), Foxq1, Hic5, Meis1a, Dab2, midkine, and the PDGF-alpha receptor. These genes are regulated specifically by RARbeta(2) in F9 wild-type (Wt) cells as indicated by their expression profiles in F9 RARbeta(2)(-/-) cells as compared to F9 Wt, RARalpha(-/-), or RARgamma(-/-) cells, and their responsiveness to specific retinoid receptor agonists. The basal expression levels of some of these genes, such as c-myc, are higher in the F9 RARbeta(2)(-/-) cells than in F9 Wt in the absence of exogenous retinoids, suggesting that RARbeta(2) can inhibit gene expression in the absence of a ligand. The RARbeta(2) target genes are transcriptionally activated by retinol, as well as RA, in F9 Wt cells. Because the lack of RARbeta(2) alters both the control of proliferation and differentiation in F9 cells, the genes that we have characterized may mediate key effects of RA, via RARbeta(2), on these processes.
Zhuang
Yong
Y
Pharmacology Department, Weill Medical College of Cornell University, New York, NY, USA.
Faria
Teresa N
TN
Chambon
Pierre
P
Gudas
Lorraine J
LJ
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D003994:Bucladesine / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors; D050993:GATA6 Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005969:Glutamate Dehydrogenase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D000078792:Midkine; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*; D018243:Teratocarcinoma; D013806:Theophylline / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; C102885:DAB2 protein, human; D004268:DNA-Binding Proteins; C484579:FOXQ1 protein, human; D051858:Forkhead Transcription Factors; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010726:Phosphodiesterase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D018168:Receptors, Retinoic Acid; C490351:TGFB1I1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C498432:ZFPM1 protein, human; C082925:retinoic acid receptor beta; D000078792:Midkine; D014212:Tretinoin; D003994:Bucladesine; D013806:Theophylline; D005969:Glutamate Dehydrogenase; D005982:Glutathione Transferase; D020796:Receptor, Platelet-Derived Growth Factor alpha