A regulatory circuit controlling Itch-mediated p73 degradation by Runx.
The members of the tumor suppressor p53 family are under tight regulation by distinct ubiquitin-protein isopeptide (E3) ligases. The level of p73 is regulated by the E3 ligase Itch. Itch levels are sharply reduced in response to DNA damage with concomitant p73 accumulation and activation. The mechanism of controlling Itch level is not known. We show that the Itch promoter is a target of the transcription activator Runx. Yes-associated protein (Yap1) is a shared transcription co-activator of Runx and p73. Under normal conditions, the Runx-Yap1 complex binds the Itch promoter and supports its transcription and p73 degradation. In response to DNA damage, Yap1 is phosphorylated by c-Abl at the position Tyr-357. The modified Yap1 does not co-activate Runx in supporting Itch transcription. The subsequent reduction in the Itch level gives rise to p73 accumulation. These results demonstrate how Yap1 supports degradation of p73 via Runx and how it plays an opposite role in response to DNA damage.
Levy
Dan
D
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100 Israel.
Reuven
Nina
N
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100 Israel.
Shaul
Yosef
Y
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100 Israel. Electronic address: Yosef.Shaul@weizmann.ac.il.
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases