SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway.

Laboratory of Vascular Biology and Gene Therapy, Centro Cardiologico Fondazione-IRCCS, Via Parea 4, 20138 Milano, Italy.
SIAH-1 and SIAH-2 are the human members of an evolutionary highly conserved E3 ligase family. SIAH-1 is a p53 and p21(Waf-1/Cip-1) induced gene during apoptosis and tumor suppression. In stable-transfected clones of MCF-7 cells, SIAH-1 overexpression was associated with apoptosis, mitotic alterations and p21(Waf-1/Cip-1) induction of expression. Using a two-hybrid screening, we identified here the transcriptional corepressor CtBP-interacting protein (CtIP) as a SIAH-1-interacting protein. CtIP has been proposed as a regulator of p21(Waf-1/Cip-1) gene transcription through a protein complex involving BRCA1. We demonstrate that SIAH-1 associates with CtIP both in vitro and in vivo. This interaction led to CtIP degradation by the ubiquitin-proteasome pathway. As expected, SIAH-1 induced p21(Waf-1/Cip-1) transcription in Jurkat-T cell. Surprisingly, a SIAH protein deleted of its RING finger, SIAH-1DeltaN, which is able to interact with CtIP but does not promote its degradation, also induced transcription from the p21(Waf-1) promoter in a similar extent as did SIAH-1. Our results suggest that p21(Waf-1/Cip-1) induction by SIAH-1 could not be mediated by CtIP degradation.
Mesh Terms:
Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, Cysteine Endopeptidases, Humans, Jurkat Cells, Multienzyme Complexes, Nuclear Proteins, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteins, Sequence Deletion, Structure-Activity Relationship, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases
Oncogene Dec. 04, 2003; 22(55);8845-51 [PUBMED:14654780]
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