Transcriptional repression of the tumor suppressor DRO1 by AIB1
ABSTRACT Using transcriptomic gene expression profiling we found tumor suppressor DRO1 being repressed in AIB1 transgenic mice. In agreement, AIB1 represses DRO1 promoter and its expression levels inversely correlate with DRO1 in several cancer cell lines and in ectopic and silencing assays. Estrogen modulators treatment showed a regulation in an estrogen receptor-dependent fashion. Importantly, DRO1 overexpression resulted in BCLAF1 upregulation, a compelling concept given that BCLAF1 is a death-promoting transcriptional repressor. Additionally, DRO1 shuttles from Golgi to the endoplasmic reticulum upon apoptotic stimuli, where it is predicted to facilitate the apoptosis cascade. Finally, DRO1 repression is an important factor for AIB1-mediated inhibition of apoptosis. Collectively, our results reveal DRO1 as an AIB1-targeted tumor suppressor, providing a novel mechanism for AIB1-dependent inhibition of apoptosis.
SourceAvailable from: Travis J Maures[Show abstract] [Hide abstract]
ABSTRACT: The tyrosine kinase Janus kinase 2 (JAK2) is activated by many cytokine receptors, including receptors for GH, leptin, and erythropoietin. However, very few proteins have been identified as binding partners for JAK2. Using a yeast 2-hybrid screen, we identified steroid-sensitive gene-1 (SSG1)/coiled-coil domain-containing protein 80 (Ccdc80) as a JAK2-binding partner. We demonstrate that Ccdc80 preferentially binds activated, tyrosyl-phosphorylated JAK2 but not kinase-inactive JAK2 (K882E) in both yeast and mammalian systems. Ccdc80 is tyrosyl phosphorylated in the presence of JAK2. The binding of Ccdc80 to JAK2 occurs via 1 or more of the 3 DUDES/SRPX (DRO1-URB-DRS-Equarin-SRPUL/sushi repeat containing protein, x-linked) domain 5 domains of Ccdc80. Mutagenesis of the second DUDES domain suggests that the N-terminal third of the DUDES domain is sufficient for JAK2 binding. Ccdc80 does not alter the kinase activity of JAK2. However, Ccdc80 increases GH-dependent phosphorylation of Stat (signal transducer and activator of transcription) 5b on Tyr699 and substantially enhances both basal and GH-dependent phosphorylation/activation of Stat3 on Tyr705. Furthermore, Ccdc80 belongs to the group of proteins that function both in the intracellular compartment and are secreted. Secreted Ccdc80 associates with the extracellular matrix and is also found in the medium. A substantial portion of the Ccdc80 detected in the medium is cleaved. Finally, consistent with the DUDES domain serving as a JAK2-binding domain, we also demonstrate that another protein that contains a DUDES domain, SRPX2, binds preferentially to the activated tyrosyl-phosphorylated form of JAK2.Molecular Endocrinology 02/2013; 27(4). DOI:10.1210/me.2011-1275 · 4.20 Impact Factor
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ABSTRACT: Context.Thyroid carcinoma is one of the most common malignancies of the endocrine system and, despite the high frequency of oncogene activation in thyroid neoplastic lesions, the tumour suppressor genes involved in thyroid carcinogenesis remain unidentified. Our previous data implicated a link between the CL2/CCDC80 gene and thyroid cancer.Objective.To examine the expression of the CL2/CCDC80 gene in human thyroid carcinomas in the attempt to determine whether it plays a role in thyroid carcinogenesis.Design.We evaluated the expression of CL2/CCDC80 in a large number of thyroid neoplastic tissue samples differing in degree of malignancy. We also investigated the effects of its restoration in two human thyroid carcinoma cell lines characterized by very low levels of CL2/CCDC80 expression.Results.CL2/CCDC80 expression was much lower in almost all the thyroid carcinomas analyzed than in normal thyroid tissues, and was lowest in follicular variants of papillary carcinomas. Loss of heterozygosity partially accounted for CL2/CCDC80 downregulation in thyroid carcinoma samples. Restoration of CL2/CCDC80 expression in the two human thyroid anaplastic carcinoma cell lines resulted in a higher susceptibility to apoptosis and suppression of the malignant phenotype. CL2/CCDC80 expression positively regulated the expression of E-cadherin thereby halting cancer progression.Conclusions.These results indicate that CL2/CCDC80 is a putative tumour suppressor gene in thyroid carcinogenesis.The Journal of Clinical Endocrinology and Metabolism 05/2013; 98(7). DOI:10.1210/jc.2012-2926 · 6.31 Impact Factor
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ABSTRACT: We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80−/− mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80−/− mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.Cancer Letters 02/2015; 357(2). DOI:10.1016/j.canlet.2014.12.010 · 5.02 Impact Factor