Negative autoregulation of p73 and p53 by DeltaNp73 in regulating differentiation and survival of human neuroblastoma cells.
p73, mapped to 1p36.2-3, is a p53-related tumor suppressor but is also induced by the oncogene products such as E2F1, raising a question whether p73 is a tumor suppressor gene or oncogene. p73 has several splicing variants including DeltaNp73 which lacks the NH(2)-terminal transactivation domain. In developing neurons, DeltaNp73 is expressed abundantly and seems to inhibit the pro-apoptotic function of p53. However, the role of TAp73 and DeltaNp73 as well as their regulatory mechanism in cell growth and differentiation of neuroblastoma cells are poorly understood. We have found that TAp73 directly activates the transcription of endogenous DeltaNp73 by binding to the TAp73-specific target element located at position-76 to 57 within the DeltaNp73 promoter region. DeltaNp73 was physically associated with TAp73alpha, TAp73beta and p53, and inhibited their transactivation activities when used reporters of Mdm2, Bax or DeltaNp73 itself in SAOS-2 cells. Overexpression of DeltaNp73 in SH-SY5Y neuroblastoma cells promoted cell survival by competing with p53 and TAp73 itself. Thus, our results suggest that the negative feedback regulation of TAp73 by its target DeltaNp73 is a novel autoregulatory system for modulating cell survival and death, that is also functioning in neuroblastoma cells.
Nakagawa
Takahito
T
Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Takahashi
Masato
M
Ozaki
Toshinori
T
Watanabe
Ken-ichi
K
Hayashi
Shunji
S
Hosoda
Mitsuchika
M
Todo
Satoru
S
Nakagawara
Akira
A
D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006706:Homeostasis; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human