Effects of pharmacologic FSH inhibition on gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE36180 | GEO | 2013/02/06
SECONDARY ACCESSION(S): PRJNA155781
REPOSITORIES: GEO
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Project description:see Super Series Summary Gene expression profiles of Drosophila S2-DRSC FSH knockdown cells were generated by Illumna RNA sequencing and compared to profiles derived from control cells (eGFP knockdown).
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Project description:see Super Series Summary Cross-linked chromatin derived from Drosophila S2-DRSC cells was immunoprecipitated using antibodies targeting ASH1 and FSH. Precipitated chromatin was sequenced applying Illumina sequencing.
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Project description:The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of ?-catenin in LH? induction by GnRH has been discovered. We examined the role of ?-catenin in FSH? gene expression in L?T2 gonadotrope cells. GnRH caused a sustained increase in nuclear ?-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of ?-catenin mRNA demonstrated that induction of FSH? mRNA by GnRH depended on ?-catenin and that regulation of FSH? by ?-catenin occurred independently of the JNK-c-jun pathway. ?-Catenin depletion had no impact on FSH? mRNA stability. In L?T2 cells transfected with FSH? promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by ?-catenin knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH. Chromatin immunoprecipitation further corroborated the absence of direct interaction between ?-catenin and the 1.8-kb FSH? promoter. To elucidate the mechanism for the ?-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing ?-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by ?-catenin knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSH? expression. Thus, our findings indicate that the expression of Brms1L depends on ?-catenin activity and contributes to FSH? induction by GnRH.
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Project description:The transcription factors STAT5A and STAT5B are essential downstream mediators of many tyrosine kinases, particularly in hematopoietic cancers. As such, STAT5 is activated by FLT3-ITD, which is a constitutively active tyrosine kinase driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 function is of significant clinical value. Here, we describe the novel small molecular weight inhibitor AC-4-130 that directly binds to the phosphotyrosine (pY)-binding pocket of the STAT5 SH2 domain, thereby disrupting STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent induction of gene transcription. AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Importantly, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. In summary, we report the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor that can efficiently block pathological levels of STAT5 activity in AML. The synergistic effects of AC-4-130 tyrosine kinase inhibitors as well as emerging treatment strategies provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
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