Transactivation-deficient p73alpha (p73Deltaexon2) inhibits apoptosis and competes with p53.
p73 has recently been identified as a structural and functional homolog of the tumor suppressor protein p53. Overexpression of p53 activates transcription of p53 effector genes, causes growth inhibition and induced apoptosis. We describe here the effects of a tumor-derived truncated transcript of p73alpha (p73Deltaexon2) on p53 function and on cell death. This transcript, which lacks the acidic N-terminus corresponding to the transactivation domain of p53, was initially detected in a neuroblastoma cell line. Overexpression of p73Deltaexon2 partially protects lymphoblastoid cells against apoptosis induced by anti-Fas antibody or cisplatin. By cotransfecting p73Deltaexon2 with wild-type p53 in the p53 null line Saos 2, we found that this truncated transcript reduces the ability of wild-type p53 to promote apoptosis. This anti-apoptotic effect was also observed when p73Deltaexon2 was co-transfected with full-length p73 (p73alpha). This was further substantiated by suppression of p53 transactivation of the effector gene p21/Waf1 in p73Deltaexon2 transfected cells and by inhibition of expression of a reporter gene under the control of the p53 promoter. Thus, this truncated form of p73 can act as a dominant-negative agent towards transactivation by p53 and p73alpha, highlighting the potential implications of these findings for p53 signaling pathway. Furthermore, we demonstrate the existence of a p73Deltaexon2 transcript in a very significant proportion (46%) of breast cancer cell lines. However, a large spectrum of normal and malignant tissues need to be surveyed to determine whether this transdominant p73 variant occurs in a tumor-specific manner.
Fillippovich
I
I
Laboratory of Molecular Radiobiology, Institute of Biophysics, Russian Ministry of Health, Moscow, 123182, Russia.
Sorokina
N
N
Gatei
M
M
Haupt
Y
Y
Hobson
K
K
Moallem
E
E
Spring
K
K
Mould
M
M
McGuckin
M A
MA
Lavin
M F
MF
Khanna
K K
KK
D017398:Alternative Splicing; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000378:metabolism
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D002945:Cisplatin