title: Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin.
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.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Shalmali Avinash
authors.initials: SA
authors.lastname: Pradhan
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Mohammad Iqbal
authors.initials: MI
authors.lastname: Rather
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Ankana
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Vishwanath Kumble
authors.initials: VK
authors.lastname: Bhat
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India karun@mrdg.iisc.ernet.in.
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
mesh_terms: D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D066260:Epiregulin; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058977:Molecular Sequence Annotation; D046912:Multiprotein Complexes / Q000378:metabolism; D019913:Nuclear Localization Signals; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; D046912:Multiprotein Complexes; D019913:Nuclear Localization Signals; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
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