Genetic regulation of cellular senescence and immortality in cultured human cells.

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The cellular senescence-associated genes that are repressed in young and immortalized cells are induced in cellular senescence and the senescent phenotypes are mediated by the functions of the senescence-associated genes. One of the senescence-associated genes, the type I collagenase gene, cary two immortaliation-susceptible cis-acting elements, ISEI and ISE2, located in a 100-bp region about 1.7kb upstream. The interplay of two ISE2-binding factors, a putative activator Pluto and a putative repressor Orpheus, was suggested to be crucial for regulation of the collagenase gene accompanying in vitro aging and immortalization.We isolated three novel cDNA clones as the candidate genes of the transcriptional activator Pluto by one hybrid screening method in yeast. The proteins coded by these cDNA clones conserve the CXXC domain of ALL-1/ML/RX complex that are located at the chromosomal breakpoints of certain leukemic cells. One of the these cDNAs encoded a protein highly related to p33NG1 tumor suppressor.The senescence-related repressor Orpheus was found to be identical to the transcription factor Oct-1. The Oct-1 protein was co-localized with a component of the nuclear lamina, lamin B,in the nuclear peripheral structure of young and immortalized cells. In senescent cells, the condensation of Oct-1 in the nuclear lamina was disappeared and the Oct-1 protein was diffusely distributed in the whole cells. Oct-1 seemed to repress the cellular senescence-associated genes by forming a heterochromatin-like higher ordered secondary structure of chromatin.Precise characterization of these immortalization-susceptible factors will give us much information concerning the intrinsic mechanism of in vitro aging and immortalization.