Regulation of p53 pathway and Tumor Growth by Novel Nucleolar Protein PICT1

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The tumor-suppressive MDM2-p53 intracellular signaling pathway is activated by cellular stress. Such stress includes DNA damage, which triggers the ATM-Chk2 and ATR-Chk1 cascades ; infection or oncogene activation, which induce t he p19ARF pathway ; and nucleolar stress, which initiates a cascade mediated by ribosomal proteins (RPs), particularly RPL5, RPL11, RPL23, and RPS7. These RPs are usually located in the nucleolus but are rapidly released into the nucleoplasm upon nucleolar stress, activating the MDM2-p53 pathway. However , it is unknown whether there are direct connections between p53-activating RP genes and cancer development in vivo, and which mechanism these RPs emplo y to translocate from the nucleolus to the nucleoplasm in response to stress . Using in vivo and in vitro experiments involving both human and murine tissues, we show that novel gene, Pict1, is a key regulator that acts thro ugh RP to control MDM2-p53 responses to nucleolar stress. In addition, Pict1 expression correlates with human colon cancer progression in human.