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: Sander Botter[Show abstract] [Hide abstract]
ABSTRACT: Osteosarcoma (OS) is a rare bone neoplasm that affects mainly adolescents. It is associated with poor prognosis in case of metastases formation. The search for metastasis predicting markers is therefore imperative to optimize treatment strategies for patients at risk and important for the search of new drugs for the treatment of this devastating disease. Here, we have analyzed by microarray the differential gene expression in four human and two mouse OS cell line systems consisting of parental cell lines with low metastatic potential and derivatives thereof with increased metastatic potential. Using two osteoblastic cell line systems, the most common OS phenotype, we have identified forty-eight common genes that are differentially expressed in metastatic cell lines compared to parental cells. The identified subset of metastasis relevant genes in osteoblastic OS overlapped only minimally with differentially expressed genes in the other four preosteoblast or nonosteoblastic cell line systems. The results imply an OS phenotype specific expression pattern of metastasis regulating proteins and form a basis for further investigation of gene expression profiles in patients' samples combined with survival analysis with the aim to optimize treatment strategies to develop new drugs and to consequently improve the survival of patients with the most common form of osteoblastic OS.Sarcoma 01/2012; 2012:937506.
Article: The role of AIB1 in breast cancer.[Show abstract] [Hide abstract]
ABSTRACT: Amplified in breast cancer 1 (AIB1) is a member of the p160 steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors including estrogen receptor (ER) and progesterone receptor (PR), as well as certain other transcription factors, including E2F1 and p53. AIB1 is widely implicated in nuclear receptor-mediated diseases, particularly malignant diseases, including breast, prostate, gastric and pancreatic cancers. AIB1 was initially implicated in hormone-dependent breast cancer, where increasing levels of AIB1 mRNA and protein were detected in some of these specimens and the overexpression of AIB1 in mice led to an increased incidence of tumors. More recent studies revealed that AIB1 also affects the growth of hormone-independent breast cancer via signaling pathways such as those of E2F1, IGF-I, EGF and PI3K/Akt/mTOR. The pleiotropic effect of AIB1 and the roles it plays in both normal development and cancer have presented a great challenge to formulating an effective therapeutic strategy for breast cancer. In this review, we highlight the significant progress made with the recent findings and present an overview of the current understanding of the influence of AIB1 on breast cancer via hormone-dependent and -independent signaling pathways.Oncology letters 10/2012; 4(4):588-594. · 0.24 Impact Factor
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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; · 4.75 Impact Factor