ARF-induced downregulation of Mip130/LIN-9 protein levels mediates a positive feedback that leads to increased expression of p16(Ink4a) and p19(Arf)

作者：Song J; Sandoval R; Pilkinton M A; Tian X; Raychaudhuri P; Colamonici O R^*

来源：Oncogene, 2010, 29(13): 1976-1986.

DOI：10.1038/onc.2009.485

• LIN-9
• ARF
• p53
• senescence and cell cycle

The ARF-MDM2-p53 pathway constitutes one of the most important mechanisms of surveillance against oncogenic transformation, and its inactivation occurs in a large proportion of cancers. Here, we show that ARF regulates Mip130/LIN-9 by inducing its translocation to the nucleolus and decreasing the expression of the Mip130/LIN-9 protein through a post-transcriptional mechanism. The knockdown of Mip130/LIN-9 in p53(-/-) and Arf(-/-) mouse embryonic fibroblasts (MEFs) mimics some effects of ARF, such as the downregulation of B-Myb, impaired induction of G2/M genes, and a decrease in cell proliferation. Importantly, although the knockdown of Mip130/LIN-9 reduced the proliferation of p53 or Arf-null MEFs, only p53(-/-) MEFs showed a senescence-like state and an increase in the expression of Arf and p16. Interestingly, the increase in p16 and ARF is indirect because the Mip130/LIN-9 knockdown decreased the transcription of negative regulators of the Ink4a/Arf locus, such as BUBR1 and CDC6. Chromatin immunoprecipitation assays also reveal that Mip130/LIN-9 occupies the promoters of the BubR1 and cdc6 genes, suggesting that Mip130/LIN-9 is necessary for the expression of these genes. Altogether, these results indicate that there is a feedback mechanism between ARF and Mip130/LIN-9 in which either the increase of ARF or the decrease in Mip130/LIN-9 causes a further increase in the expression of Arf and p16. Oncogene (2010) 29, 1976-1986; doi:10.1038/onc.2009.485; published online 18 January 2010

• 出版日期2010-4
• 单位西北大学