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Id1 induces apoptosis through inhibition of RORgammat expression.

ABSTRACT: 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.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.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.

SUBMITTER: Yang Y

PROVIDER: S-EPMC2408562 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Id1 induces apoptosis through inhibition of RORgammat expression.

Yang Yuanzheng Y Wang Hong-Cheng HC Sun Xiao-Hong XH

BMC immunology 20080519

<h4>Background</h4>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 knowledg ...[more]

PMID: 18489764

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Project description:BackgroundCD44 is a molecular marker associated with cancer stem cell populations and treatment resistance in glioma. More effective therapies will result from approaches aimed at targeting glioma cells high in CD44.MethodsGlioma-initiating cell lines were derived from fresh surgical glioblastoma samples. Expression of tissue transglutaminase 2 (TGM2) was attenuated through lentivirus-mediated short hairpin RNA knockdown. MTT assay [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] was used to evaluate the growth inhibition induced by TGM2 inhibitor. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling was used to evaluate cell apoptosis following TGM2 inhibition. CD44(+) glioma stem cells were sorted by flow cytometry. A nude mice orthotopic xenograft model was used to evaluate the in vivo effect of TGM2 inhibitor.ResultsTGM2 was highly expressed in CD44-high glioblastoma tissues and tumor-derived glioma-initiating cell lines. TGM2 knockdown impaired cell proliferation and induced apoptosis in CD44-high glioma-initiating cell lines. Further studies indicated that expression of inhibitor of DNA binding 1 protein (ID1) is regulated by TGM2 and might be an important mediator for TGM2-regulated cell proliferation in CD44-high glioma-initiating cell lines. TGM2 inhibitor reduces ID1 expression, suppresses cell proliferation, and induces apoptosis in CD44-high glioma-initiating cell lines. Furthermore, TGM2 is highly expressed in CD44(+) glioma stem cells, while pharmacological inhibition of TGM2 activity preferentially eliminates CD44(+) glioma stem cells. Consistently, TGM2 inhibitor treatment reduced ID1 expression and induced apoptosis in our orthotopic mice xenograft model, which can be translated into prolonged median survival in tumor-bearing mice.ConclusionsTGM2 regulates ID1 expression in glioma-initiating cell lines high in CD44. Targeting TGM2 could be an effective strategy to treat gliomas with high CD44 expression.

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Id1 induces apoptosis through inhibition of RORgammat expression.

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Id1 induces apoptosis through inhibition of RORgammat expression.

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