ABSTRACT
The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.
Subject(s)
Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA-Binding Proteins/physiology , Genes, ras , Oncogene Proteins/physiology , Animals , Cell Cycle Proteins/physiology , Cell Differentiation , Cell Line , Cell Proliferation , Cell Transformation, Neoplastic , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Mice , Mice, Inbred C57BL , Molecular Chaperones , RNA-Binding Proteins , Tretinoin/pharmacologyABSTRACT
Bladder cancer is a major cause of health expenses and it presents formidable clinical challenges. Two types of tumors have been identified, papillary and non-papillary. The former are mainly characterized by FGFR3 and chromosome 9 alterations and a low frequency of Tp53 alterations. The latter are characterized by a high frequency of alterations in genes in the p53 and Rb pathways. Chromosome 9 alterations, specially in 9q, are crucial to bladder cancer development and occur in both types of tumors. Progression of some superficial tumors (mainly TaG3 and T1G3) to high-grade, invasive, carcinomas provides evidence of some overlap between the two pathways. Distinct gene expression profiles have been identified in superficial and invasive tumors. The stage is now ready for the clinical application of this knowledge (AU)
