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Origins of G 1 arrest in senescent human fibroblasts
Author(s) -
Stein Gretchen H.,
Dulić Vjekoslav
Publication year - 1995
Publication title -
bioessays
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.175
H-Index - 184
eISSN - 1521-1878
pISSN - 0265-9247
DOI - 10.1002/bies.950170610
Subject(s) - biology , cell cycle , microbiology and biotechnology , retinoblastoma protein , dna damage , cyclin , telomere , dna synthesis , kinase , cyclin d , signal transduction , senescence , cyclin dependent kinase 4 , gene , protein kinase a , cyclin dependent kinase 2 , dna , genetics
Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are ararrested with G 1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c‐fos. Later in G 1 , they uniformly fail to express late G 1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin‐dependent kinase inhibitor whose levels are also elevated in cells arrested in G 1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactivate the cell cycle machinery.