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Molecular and Cellular Biology, December 2004, p. 10792-10801, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10792-10801.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Genetic Screen for Genes Involved in Senescence: Role of Tid1, a Homologue of the Drosophila Tumor Suppressor l(2)tid, in Senescence and Cell Survival

Marina Tarunina,1 Lynsey Alger,2 Grace Chu,1 Karl Munger,3 Andrei Gudkov,4 and Parmjit S. Jat1,5*

Ludwig Institute for Cancer Research, University College Branch of Cell and Molecular Biology,1 Department of Biochemistry and Molecular Biology,2 Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, United Kingdom,5 Department of Pathology and Harvard Center for Cancer Biology, Harvard Medical School, Boston, Massachusett,3 Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio4

Received 22 March 2004/ Returned for modification 3 May 2004/ Accepted 17 September 2004

We performed a genetic suppressor element screen to identify genes whose inhibition bypasses cellular senescence. A normalized library of fragmented cDNAs was used to select for elements that promote immortalization of rat embryo fibroblasts. Fragments isolated by the screen include those with homology to genes that function in intracellular signaling, cellular adhesion and contact, protein degradation, and apoptosis. They include mouse Tid1, a homologue of the Drosophila tumor suppressor gene l(2)tid, recently implicated in modulation of apoptosis as well as gamma interferon and NF-{kappa}B signaling. We show that GSE-Tid1 enhances immortalization by human papillomavirus E7 and simian virus 40 T antigen and cooperates with activated ras for transformation. Expression of Tid1 is upregulated upon cellular senescence in rat and mouse embryo fibroblasts and premature senescence of REF52 cells triggered by activated ras. In accordance with this, spontaneous immortalization of rat embryo fibroblasts is suppressed upon ectopic expression of Tid1. Modulation of endogenous Tid1 activity by GSE-Tid1 or Tid1-specific RNA interference alleviates the suppression of tumor necrosis factor alpha-induced NF-{kappa}B activity by Tid1. We also show that NF-{kappa}B sequence-specific binding is strongly downregulated upon senescence in rat embryo fibroblasts. We therefore propose that Tid1 contributes to senescence by acting as a repressor of NF-{kappa}B signaling.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, 91 Riding House St., London W1W 7BS, United Kingdom. Phone: 44 207 878 4099. Fax: 44 207 878 4040. E-mail: parmjit{at}ludwig.ucl.ac.uk.

Molecular and Cellular Biology, December 2004, p. 10792-10801, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10792-10801.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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