A novel androgen-regulated isoform of the TSC2 tumour suppressor gene increases cell proliferation
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Jennifer Munkley1, Prabhakar Rajan2,3, Nicholas P. Lafferty1, Caroline Dalgliesh1, Robert M. Jackson1, Craig N. Robson4, Hing Y. Leung2,3 and David J. Elliott1
1 Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, United Kingdom,
2 Beatson Institute for Cancer Research, Glasgow, United Kingdom,
3 Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom,
4 Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
David J. Elliott, email:
Jennifer Munkley, email:
Keywords: TSC2, mTOR, mRNA isoform, androgen, prostate cancer
Received: September 11, 2013 Accepted: October 19, 2013 Published: October 21, 2013
TSC2 (Tuberous sclerosis complex 2) is an important tumour suppressor gene, mutations within which are linked to the development of tuberous sclerosis and implicated in multiple tumour types. TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth. Here, we report the characterisation of a novel isoform of TSC2 which is under direct control of the ligand-activated androgen receptor. TSC2 isoform A (TSC2A) is derived from an internal androgen-regulated alternative promoter and encodes a 508-amino acid cytoplasmic protein corresponding to the C-terminal region of full-length TSC2, lacking the interaction domain for TSC1 and containing an incomplete interaction domain required for Rheb inactivation. Expression of TSC2A is induced in response to androgens and full-length TSC2 is co-ordinately down-regulated, indicating an androgen-driven switch in TSC2 protein isoforms. In contrast to the well-characterised suppressive effect on cell proliferation of full-length TSC2 protein, both LNCaP and HEK293 cells over-expressing TSC2 isoform A proliferate more rapidly (measured by MTT assays) and have increased levels of cells in S-phase (measured by both Edu staining and FACS analysis). Our work indicates, for the first time, a novel role for this well-known tumour suppressor gene, which encodes an activator of cell proliferation in response to androgen stimulation.
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