Cellular senescence and chromatin structure.
Cellular senescence is characterized by stable cell cycle arrest that is triggered by various forms of stress stimuli. Senescent cells show a series of morphological and physiological alterations including a flat and enlarged morphology, an increase in acidic beta-galactosidase activity, chromatin condensation, and changes in gene expression pattern. These features are not observed in proliferating cells or quiescent cells in vitro. Using these senescence markers, cellular senescence has been shown to occur in benign or premalignant lesions but not in malignant lesions and to act as a tumor-suppressing mechanism in vivo. The onset and maintenance of the senescent state are regulated by two tumor suppressor proteins, p53 and Rb, which mediate senescence signals through p38 mitogen-activated protein kinase and cyclin-dependent kinase inhibitors. Alterations of chromatin structure are believed to contribute to the irreversible nature of the senescent state. Senescent cells form characteristic heterochromatin structure called senescence-associated heterochromatic foci (SAHFs), which may repress the expression of proliferation-promoting genes, such as E2F target genes. Recent studies have provided molecular insights into the structure and the mechanism of SAHF formation. In this paper, we review the role of cellular senescence in tumor suppression in vivo and the molecular mechanism of stable growth arrest in senescent cells, focusing on the special form of heterochromatin, SAHFs.
Funayama
Ryo
R
Laboratory of Cell Cycle Regulation, Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Kyoto, 606-8501, Japan.
Ishikawa
Fuyuki
F
D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006570:Heterochromatin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D012097:Repressor Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D006570:Heterochromatin; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases