Defective ATM-p53-mediated apoptotic pathway in multiple sclerosis.
Defective elimination of autoreactive cells is thought to play a role in the development of autoimmune diseases including multiple sclerosis (MS). We examined the activation of the ATM-CHK2-p53 pathway in MS patients after subjecting their peripheral blood mononuclear cells to gamma-irradiation. We found that peripheral blood mononuclear cells from a subset of MS patients show resistance to cell death induced by irradiation. This defect is due to impaired constitutive expression and activation of ATM (ataxia telangiectasia mutated), resulting in impaired stabilization of p53. We predict that these fundamental defects likely alter the regulation of the immune population of cells in MS and may contribute to the development or progression of the disease.
Deng
Xinqing
X
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. xinqing.deng@vanderbilt.edu
Ljunggren-Rose
Asa
A
Maas
Kevin
K
Sriram
Subramaniam
S
D000328:Adult; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000145:classification / Q000473:pathology / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases