title: Rapamycin and p53 act on different pathways to induce G1 arrest in mammalian cells.
abstract: Certain growth regulatory kinases contain a common domain related to the phospho-inositol 3 (PI-3) kinase catalytic site. These include the ATM gene product, DNA-PKcs, and the target of rapamycin (TOR in yeast; and FRAP in mammalian cells). Rapamycin inhibits growth factor signalling and induces G1 arrest in many cell types. Some growth regulatory PI-3 kinases appear functionally linked to p53 and we have explored potential links between cellular effects induced by rapamycin and p53. In p53 null cells rapamycin inhibited cell cycling but did not induce G1 arrest. In cells which showed selective G1 arrest in response to rapamycin, rapamycin had no effect on basal levels of p53 protein. Similarly p21(WAF1) protein was not induced by rapamycin. The kinetics of the cellular p53/p21(WAF1) response to ionising radiation was unaffected by rapamycin; and the ability of growth factor to protect against p53-mediated apoptosis in response to DNA damage was also unaffected by rapamycin. The ATM gene is mutated in the cancer susceptibility syndrome ataxia telangiectasia (AT) but such mutant cells showed a similar sensitivity to rapamycin compared to their normal counterparts. RKO cell lines of common genetic background, but with different levels of functional p53 protein, also responded similarly to rapamycin. Thus, although rapamycin and p53 are each able to induce G1 arrest, they appear to act through independent growth regulatory pathways.
authors.affiliation: Department of Surgery, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Metcalfe
authors.forename: C E
authors.initials: CE
authors.lastname: Canman
authors.forename: J
authors.initials: J
authors.lastname: Milner
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
authors.forename: S
authors.initials: S
authors.lastname: Goldman
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D016193:G1 Phase; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D020104:Immunophilins; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D020104:Immunophilins; D007377:Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse