Ascochlorin activates p53 in a manner distinct from DNA damaging agents.
Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins.
Jeong
Ji-Hak
JH
Research Institute of Biomedical Engineering, Catholic University of Daegu School of Medicine, Daegu, Korea.
Nakajima
Hiroo
H
Magae
Junji
J
Furukawa
Chiharu
C
Taki
Keiko
K
Otsuka
Kensuke
K
Tomita
Masanori
M
Lee
In-Seon
IS
Kim
Cheorl-Ho
CH
Chang
Hyeun-Wook
HW
Min
Kwan-Sik
KS
Park
Kwang-Kyun
KK
Park
Kwan-Kyu
KK
Chang
Young-Chae
YC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000475:Alkenes / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010636:Phenols; D012333:RNA, Messenger; D012717:Sesquiterpenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C006640:ascofuranone; C415745:ascochlorin