Molecular aspects of cellular senescence in human diploid fibroblasts

摘要

A growing body of knowledge supports the idea that the replicative lifespan of individual cells is closely related to the in vivo lifespan of humans. Cultured human diploid fibroblasts normally undergo a limited number of population doublings before they activate an intrinsic growth-limiting program culminating in cellular senescence. Molecular studies of this aging program have begun to reveal some details of the underlying mechanisms and have suggested how their abrogation contributes to cellular immortalization and tumorigenesis. This review examines the role of some positive and negative growth-regulatory processes in the human diploid fibroblast model of cellular senescence that are being examined in our group. Evidence that hyperphosphorylation of serum response factor underlies the senescence-associated loss of Fos transcription factor activity is discussed. The role of key regulators of cell-cycle progression in senescence is reviewed, including the elevated expression of D-type cyclins and the augmented expression and/or activity of 'tumor suppressor' genes whose functions are lost in tumorigenesis. The role and regulation of attrition of telomeres in the initiation of the senescent state is also discussed. [References: 89]