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Molecular and Cellular Biology, December 2002, p. 8155-8164, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8155-8164.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Normal p53 Function in Primary Cells Deficient for Siah Genes

Ian J. Frew,1 Ross A. Dickins,1 Andrew R. Cuddihy,1 Merci Del Rosario,2 Christoph Reinhard,2 Matthew J. O'Connell,1,3 and David D. L. Bowtell4*

Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002,1 Department of Genetics,3 Department of Biochemistry, University of Melbourne, Parkville, Victoria 3010, Australia,4 Chiron Corporation, 94608 Emeryville, California2

Received 19 June 2002/ Returned for modification 2 August 2002/ Accepted 6 September 2002

Overexpression studies have suggested that Siah1 proteins may act as effectors of p53-mediated cellular responses and as regulators of mitotic progression. We have tested these hypotheses using Siah gene knockout mice. Siah1a and Siah1b were not induced by activation of endogenous p53 in tissues, primary murine embryonic fibroblasts (MEFs) or thymocytes. Furthermore, primary MEFs lacking Siah1a, Siah1b, Siah2, or both Siah2 and Siah1a displayed normal cell cycle progression, proliferation, p53-mediated senescence, and G1 phase cell cycle arrest. Primary thymocytes deficient for Siah1a, Siah2, or both Siah2 and Siah1a, E1A-transformed MEFs lacking Siah1a, Siah1b, or Siah2, and Siah1b-null ES cells all underwent normal p53-mediated apoptosis. Finally, inhibition of Siah1b expression in Siah2 Siah1a double-mutant cells failed to inhibit cell division, p53-mediated induction of p21 expression, or cell cycle arrest. Our loss-of-function experiments do not support a general role for Siah genes in p53-mediated responses or mitosis.

* Corresponding author. Mailing address: Peter MacCallum Cancer Institute, St. Andrews Pl., East Melbourne, Victoria 3002, Australia. Phone: 61 3 9656 1296. Fax: 61 3 9656 1411. E-mail: d.bowtell{at}pmci.unimelb.edu.au.

Molecular and Cellular Biology, December 2002, p. 8155-8164, Vol. 22, No. 23
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.23.8155-8164.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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