Genetic Control of Cell Senescence in Carcinogenesis

Aging is characterized by reduced repair and regeneration of damaged or lost cells. The expression of p16INK4a and ARF increased markedly with aging in human and rodents. Therefore, p16INK4a and ARF are considered as biomarkers of aging. Cell senescence is a specialized form of terminal differentiation characterized by an upregulated senescence-associated-β-galactosidase activity and formation of senescence-associated heterochromatin foci (SAHF), and is generally permanent. Recent studies have demonstrated that senescence is associated with SAHF formation, leading to the accumulation of heterochromatin protein 1 (HP1) and histone H3 trimethylated on lysine 9 (me-K9H3) in SAHF. HMGA1 and HMGA2 specially accumulate on senescent cell chromatin areas that contain me-K9H3 and HP1. In addition, HMGA proteins cooperate with p16INK4a to promote SAHF formation and proliferation arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. The decision to enter cellular senescence is determined by a histone methyltransferase (HMT) that acts with RB and HP1 protein to alter chromatin structure and silence E2F. p53 and RB pathway may function as a natural brake to tumor development by maintaining cellular senescence. Rb contributes to senescence by promoting SAHF formation cooperated with HMGA and silencing E2F target genes. Upregultion of p16 during senescence engages the Rb pathway to produce a permanent arrest by altering the chromatin state of growth regulatory genes. Failure of these processes may lead to cancer progression. The stable maintenance of growth is critical for the contribution of cell senescence to tumor suppression. Chromatin structure alteration should account for the irreversible nature of the senescence state. To date, there is no report that links the cellular senescence states to the leukemogenesis. Since senescence is considered as a defining feature of premalignant tumors, the role of genetic control of cell senescence in leukemognesis will be investigated in this project. We plan to investigate if the disruption of cell senescence state will lead to the progression of carcinogenesis. In addition, the molecular basis for the stability maintenance and disruption of cell senescence states will also be investigated.

Project ID:PC9801-1453
External Project ID:NSC96-2320-B182-037-MY3