Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses.

Destruction of beta-catenin is regulated through phosphorylation-dependent interactions with the F box protein beta-TrCP. A novel pathway for beta-catenin degradation was discovered involving mammalian homologs of Drosophila Sina (Siah), which bind ubiquitin-conjugating enzymes, and Ebi, an F box protein that binds beta-catenin independent of the phosphorylation sites recognized by beta-TrCP. A series of protein interactions were identified in which Siah is physically linked to Ebi by association with a novel Sgt1 homolog SIP that binds Skp1, a central component of Skp1-Cullin-F box complexes. Expression of Siah is induced by p53, revealing a way of linking genotoxic injury to destruction of beta-catenin, thus reducing activity of Tcf/LEF transcription factors and contributing to cell cycle arrest.

[1]  Mark Peifer,et al.  Signal transduction: Neither straight nor narrow , 1999, Nature.

[2]  H Clevers,et al.  TCF/LEF factor earn their wings. , 1997, Trends in genetics : TIG.

[3]  D. Bowtell,et al.  Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Israeli,et al.  Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. White,et al.  Tumor Suppressing Pathways , 1998, Cell.

[6]  G. Rubin,et al.  seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye , 1990, Cell.

[7]  M. Peifer,et al.  Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus. , 2000, Science.

[8]  S. Zipursky,et al.  ebi regulates epidermal growth factor receptor signaling pathways in Drosophila. , 1999, Genes & development.

[9]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[10]  S. Elledge,et al.  How the Cyclin Became a Cyclin Regulated Proteolysis in the Cell Cycle , 1999, Cell.

[11]  K. Staehling-Hampton,et al.  A role for Ebi in neuronal cell cycle control , 2000, The EMBO journal.

[12]  E. Fearon,et al.  Siah-1 N-Terminal RING Domain Is Required for Proteolysis Function, and C-Terminal Sequences Regulate Oligomerization and Binding to Target Proteins , 1999, Molecular and Cellular Biology.

[13]  S. Elledge,et al.  SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. , 1999, Molecular cell.

[14]  Stephen J. Elledge,et al.  The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro , 1999 .

[15]  Raymond L. White,et al.  Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. , 2001, Molecular cell.

[16]  John Calvin Reed,et al.  Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. , 1994, Oncogene.

[17]  John Calvin Reed,et al.  p53‐inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG‐1 , 1998, The EMBO journal.

[18]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[19]  T. P. Neufeld,et al.  PHYL Acts to Down-Regulate TTK88, a Transcriptional Repressor of Neuronal Cell Fates, by a SINA-Dependent Mechanism , 1997, Cell.

[20]  M. Clarke,et al.  Cell cycle analysis of p53-induced cell death in murine erythroleukemia cells , 1993, Molecular and cellular biology.

[21]  L. Piouffre,et al.  p21WAF-1 reorganizes the nucleus in tumor suppression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Israeli,et al.  SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1). , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Vidal,et al.  Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway. , 1997, Genes & development.

[24]  John Calvin Reed,et al.  R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl- 2 suppressible mechanism , 1995, The Journal of cell biology.

[25]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[26]  A. Look,et al.  Characterization of human homologs of the Drosophila seven in absentia (sina) gene. , 1997, Genomics.

[27]  R. Brent,et al.  Correlation of two-hybrid affinity data with in vitro measurements , 1995, Molecular and cellular biology.

[28]  John Calvin Reed,et al.  BAG‐1 modulates the chaperone activity of Hsp70/Hsc70 , 1997, The EMBO journal.

[29]  John Calvin Reed,et al.  p53 Suppresses the c-Myb-induced Activation of Heat Shock Transcription Factor 3* , 2000, The Journal of Biological Chemistry.

[30]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.