PMID- 12907682 OWN - NLM STAT- MEDLINE DCOM- 20040105 LR - 20210206 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 278 IP - 43 DP - 2003 Oct 24 TI - A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4. PG - 42637-42 AB - Steroidogenic factor 1 (SF-1) is a transcription factor belonging to the nuclear receptor superfamily. SF-1 regulates the expression of many genes involved in reproduction, steroidogenesis, and sexual differentiation. An important SF-1 target for male sexual differentiation is the gene encoding the Mullerian-inhibiting substance hormone that induces regression of the Mullerian ducts in the developing male embryo. Not long ago, a mutation (G35E) in the human SF-1 gene was identified as the cause of sex reversal and adrenal failure in a phenotypically female but genotypically XY individual. This suggested that the mutated SF-1 protein might interfere with the expression of SF-1 target gene(s) involved in the male sexual differentiation pathway, such as MIS. Surprisingly, the initial biochemical characterization of the SF-1 G35E mutant revealed that it could bind and activate the MIS promoter as efficiently as wild-type SF-1. MIS expression, however, does not rely solely on SF-1 but rather requires the concerted action of several transcription factors including GATA-4. We have previously reported that GATA-4 and SF-1 transcriptionally cooperate to synergistically activate the MIS promoter. Thus, we hypothesized that the phenotype observed with the SF-1 G35E mutation could be explained, at least in part, by a failure and/or a disruption of GATA-4/SF-1 synergism. We found that the SF-1 G35E mutant failed to synergize with GATA-4 despite a direct physical interaction between the two proteins. Interestingly, the SF-1 G35E mutant also disrupted transcriptional synergism between wild-type SF-1 and GATA-4, indicating that it could act as a dominant negative competitor. Thus, our results strengthen the importance of a GATA-4/SF-1 cooperation for MIS transcription and reveal that disruption of this synergism might be responsible for some cases of abnormal sex differentiation in humans. FAU - Tremblay, Jacques J AU - Tremblay JJ AD - Ontogeny-Reproduction Research Unit, CHUL Research Centre and Centre de Recherche en Biologie de la Reproduction, Department of Obstetrics and Gynecology, Universite Laval, 2705 Laurier Boulevard, Sainte-Foy, Quebec G1V 4G2, Canada. FAU - Viger, Robert S AU - Viger RS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20030806 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (DNA-Binding Proteins) RN - 0 (Fushi Tarazu Transcription Factors) RN - 0 (GATA4 Transcription Factor) RN - 0 (Glycoproteins) RN - 0 (Homeodomain Proteins) RN - 0 (NR5A1 protein, human) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 0 (Steroidogenic Factor 1) RN - 0 (Testicular Hormones) RN - 0 (Transcription Factors) RN - 0 (steroidogenic factor 1, mouse) RN - 0 (steroidogenic factor 1, rat) RN - 80497-65-0 (Anti-Mullerian Hormone) SB - IM MH - Animals MH - Anti-Mullerian Hormone MH - Cell Line MH - DNA-Binding Proteins/*genetics/*physiology MH - *Disorders of Sex Development MH - Drug Synergism MH - Fushi Tarazu Transcription Factors MH - GATA4 Transcription Factor MH - Glycoproteins/genetics MH - Homeodomain Proteins MH - Humans MH - Male MH - Mice MH - *Mutation, Missense MH - Promoter Regions, Genetic MH - Protein Binding MH - Rats MH - Receptors, Cytoplasmic and Nuclear MH - Steroidogenic Factor 1 MH - Testicular Hormones/genetics MH - Transcription Factors/*genetics/*physiology MH - Transcription, Genetic MH - Transfection EDAT- 2003/08/09 05:00 MHDA- 2004/01/06 05:00 CRDT- 2003/08/09 05:00 PHST- 2003/08/09 05:00 [pubmed] PHST- 2004/01/06 05:00 [medline] PHST- 2003/08/09 05:00 [entrez] AID - S0021-9258(20)82808-7 [pii] AID - 10.1074/jbc.M305485200 [doi] PST - ppublish SO - J Biol Chem. 2003 Oct 24;278(43):42637-42. doi: 10.1074/jbc.M305485200. Epub 2003 Aug 6.