title: Id1 induces apoptosis through inhibition of RORgammat expression.
abstract: BACKGROUND
  Basic helix-loop-helix E proteins are transcription factors that play crucial roles in T cell development by controlling thymocyte proliferation, differentiation and survival. E protein functions can be repressed by their naturally occurring inhibitors, Id proteins (Id1-4). Transgenic expression of Id1 blocks T cell development and causes massive apoptosis of developing thymocytes. However, the underlying mechanisms are not entirely understood due to relatively little knowledge of the target genes regulated by E proteins.
  
  
  RESULTS
  We designed a unique strategy to search for genes directly controlled by E proteins and found RORgammat to be a top candidate. Using microarray analyses and reverse-transcriptase PCR assays, we showed that Id1 expression diminished RORgammat mRNA levels in T cell lines and primary thymocytes while induction of E protein activity restored RORgammat expression. E proteins were found to specifically bind to the promoter region of RORgammat, suggesting their role in activating transcription of the gene. Functional significance of E protein-controlled RORgammat expression was established based on the finding that RORgammat rescued apoptosis caused by Id1 overexpression. Furthermore, expression of RORgammat prevented Id1-induced p38 MAP kinase hyper-activation.
  
  
  CONCLUSIONS
  These results suggest that E protein-dependent RORgammat gene expression aids the survival of developing thymocytes, which provides a possible explanation for the massive apoptosis found in Id1 transgenic mice.
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104, USA. yuayang@utmb.edu
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Hong-Cheng
authors.initials: HC
authors.lastname: Wang
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020411:Oligonucleotide Array Sequence Analysis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D058125:Transcription Factor 7-Like 1 Protein; D014161:Transduction, Genetic
chemical_list: C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; C539901:Rorc protein, mouse; D051820:TCF Transcription Factors; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D013629:Tamoxifen