Normal p53 function in primary cells deficient for Siah genes.
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 G(1) 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.
Frew
Ian J
IJ
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia.
Dickins
Ross A
RA
Cuddihy
Andrew R
AR
Del Rosario
Merci
M
Reinhard
Christoph
C
O'Connell
Matthew J
MJ
Bowtell
David D L
DD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins; D013234:Stem Cells / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C484442:Siah1a protein, mouse; C484443:Siah1b protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins