Analysis of Apaf-1 and Caspase 9 in Tumorigenesis
Abstract
The replicative exhaustion of Human diploid fibroblasts (HDFs) in culture is associated with an "irreversible" cell-cycle arrest known as replicative senescence. However, young cells can enter a similar phenotype to replicative senescence in response to expression of certain mitogenic oncogenes, oxidative stress, and DNA damage. Cellular senescence involves activation of the p53 and pl6/Rb tumor suppressor pathways. We identified a novel type of chromatin structure that has features of heterochromatin and appears to contribute to the senescence state. We designated these chromatin structures as SAHFs, Senescence Associated Heterochromatic Foci. SAHF formation is dependent on the p16/Sb pathway, which is often abrogated in breast cancer. We also showed that some cell-cycle genes are stably silenced in senescence. Here we further characterized SAHFs and found the distinct localization polycomb (some PcG proteins are implicated in pl6 regulation) in SAHFs. Moreover, we found that enforced expression of SUV39Hl (a histone H3 lysine 9 methyltransferase; HMT)%, which can form complex with Rb, induced senescence like phenotype in HDFs, which underscores importance of chromatin modifications in senescence. We propose that Rb-dependent changes in chromatin organization are critical in senescence and some HMT and PcG might be involved in SAHF formation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA427134
Entities
People
- Masashi Narita
Organizations
- Cold Spring Harbor Laboratory