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Molecular and Cellular Biology, September 2007, p. 6068-6083, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00664-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Arkadia Activates Smad3/Smad4-Dependent Transcription by Triggering Signal-Induced SnoN Degradation{triangledown} ,{dagger}

Laurence Levy,1 Michael Howell,1 Debipriya Das,1 Sean Harkin,1 Vasso Episkopou,2 and Caroline S. Hill1*

Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom,1 Mammalian Neurogenesis, MRC Clinical Sciences Centre, Imperial School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom2

Received 16 April 2007/ Returned for modification 25 May 2007/ Accepted 14 June 2007

E3 ubiquitin ligases play important roles in regulating transforming growth factor ß (TGF-ß)/Smad signaling. Screening of an E3 ubiquitin ligase small interfering RNA library, using TGF-ß induction of a Smad3/Smad4-dependent luciferase reporter as a readout, revealed that Arkadia is an E3 ubiquitin ligase that is absolutely required for this TGF-ß response. Knockdown of Arkadia or overexpression of a dominant-negative mutant completely abolishes transcription from Smad3/Smad4-dependent reporters, but not from Smad1/Smad4-dependent reporters or from reporters driven by Smad2/Smad4/FoxH1 complexes. We show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN. Arkadia is essential for TGF-ß-induced SnoN degradation, but it has little effect on SnoN levels in the absence of signal. Arkadia interacts with SnoN and induces its ubiquitination irrespective of TGF-ß/Activin signaling, but SnoN is efficiently degraded only when it forms a complex with both Arkadia and phosphorylated Smad2 or Smad3. Finally, we describe an esophageal cancer cell line (SEG-1) that we show has lost Arkadia expression and is deficient for SnoN degradation. Reintroduction of wild-type Arkadia restores TGF-ß-induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer.

* Corresponding author. Mailing address: Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44-20-7269-2941. Fax: 44-20-7269-3093. E-mail: caroline.hill{at}cancer.org.uk

{triangledown} Published ahead of print on 25 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2007, p. 6068-6083, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00664-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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