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Pradhan, SA; Rather, MI; Tiwari, A; Bhat, VK; Kumar, A.
Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin.
Nucleic Acids Res. 2014; 42(10): 6243-6255. Doi: 10.1093/nar/gku278 [OPEN ACCESS]
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Co-authors Med Uni Graz: Bhat Kumble Vishwanath
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Abstract:: The TSC2 gene, mutated in patients with tuberous sclerosis complex (TSC), encodes a 200 kDa protein TSC2 (tuberin). The importance of TSC2 in the regulation of cell growth and proliferation is irrefutable. TSC2 in complex with TSC1 negatively regulates the mTOR complex 1 (mTORC1) via RHEB in the PI3K-AKT-mTOR pathway and in turn regulates cell proliferation. It shows nuclear as well as cytoplasmic localization. However, its nuclear function remains elusive. In order to identify the nuclear function of TSC2, a whole-genome expression profiling of TSC2 overexpressing cells was performed, and the results showed differential regulation of 266 genes. Interestingly, transcription was found to be the most populated functional category. EREG (Epiregulin), a member of the epidermal growth factor family, was found to be the most downregulated gene in the microarray analysis. Previous reports have documented elevated levels of EREG in TSC lesions, making its regulatory aspects intriguing. Using the luciferase reporter, ChIP and EMSA techniques, we show that TSC2 binds to the EREG promoter between -352 bp and -303 bp and negatively regulates its expression. This is the first evidence for the role of TSC2 as a transcription factor and of TSC2 binding to the promoter of any gene. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Find related publications in this database (using NLM MeSH Indexing): Cell Line, Tumor -; Epidermal Growth Factor - biosynthesis Epidermal Growth Factor - genetics; Epiregulin -; Gene Expression Regulation -; Gene Regulatory Networks -; Humans -; Molecular Sequence Annotation -; Multiprotein Complexes - metabolism; Nuclear Localization Signals -; Promoter Regions, Genetic -; Repressor Proteins - antagonists & inhibitors Repressor Proteins - chemistry Repressor Proteins - metabolism; TOR Serine-Threonine Kinases - metabolism; Transcription, Genetic -; Tumor Suppressor Proteins - antagonists & inhibitors Tumor Suppressor Proteins - chemistry Tumor Suppressor Proteins - metabolism