title: Bimodal regulation of p21(waf1) protein as function of DNA damage levels.
abstract: Human p21(Waf1) protein is well known for being transcriptionally induced by p53 and activating the cell cycle checkpoint arrest in response to DNA breaks. Here we report that p21(Waf1) protein undergoes a bimodal regulation, being upregulated in response to low doses of DNA damage but rapidly and transiently degraded in response to high doses of DNA lesions. Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis. The initial p21(Waf1) degradation is then counteracted by the ATM-Chk2 pathway, which promotes the p53-dependent accumulation of p21(Waf1) at any dose of damage. We also found that p21(Waf1) ablation favors the activation of an apoptotic program to eliminate otherwise irreparable cells. These findings support a model in which in human cells a balance between ATM-Chk2-p53 and the ATR-Chk1 pathways modulates p21(Waf1) protein levels in relation to cytostatic and cytotoxic doses of DNA damage.
authors.affiliation: a Department of Experimental Oncology; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan , Italy.
authors.forename: G
authors.initials: G
authors.lastname: Buscemi
authors.forename: C
authors.initials: C
authors.lastname: Ricci
authors.forename: L
authors.initials: L
authors.lastname: Zannini
authors.forename: E
authors.initials: E
authors.lastname: Fontanella
authors.forename: P
authors.initials: P
authors.lastname: Plevani
authors.forename: D
authors.initials: D
authors.lastname: Delia
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D001761:Bleomycin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: BLM, bleomycin; DDR, DNA damage response; DSBs, double strand breaks; FCS, fetal calf serum; IF, immunofluorescence; apoptosis, cell survival, DNA damage response, double strand breaks