Stress-induced senescence: Molecular pathways

Senescence is an irreversible state of the cell, in which the cell becomes incapable of further cell division. The concept of stress-induced senescence indicates that the major causes of senescence are various types of stresses that act on cells. These stresses act via intracellular pathways, which may be multiple, to a final common state of irreversible cell division. In this state the cell is held in the nondividing state by the combination of cyclin-dependent kinase inhibitor (CDKI) activity, heterochromatin formation, gene expression changes, and other mechanisms. While the mediators of stressinduced senescence are multiple and complex, the p38 MAP kinase pathway has a prominent role in linking stresses to the permanently nondividing state. The means by which it may become activated by stresses and the means by which it acts to cause senescence are being unraveled. While most of the past studies on senescence have used cells in culture, the recent emergence of novel mouse models in which senescence can be studied has opened up exciting avenues toward mechanistic insights and possible therapeutic interventions.