p51/p63, a novel p53 homologue, potentiates p53 activity and is a human cancer gene therapy candidate.
BACKGROUND
p51 (p73L/p63/p40/KET), a recently isolated novel p53 homologue, binds to p53-responsive elements to upregulate some p53 target genes and has been suggested to share partially overlapping functions with p53. p51 may be a promising candidate target molecule for anti-cancer therapy.


METHODS
In this study, we adenovirally transduced p51A cDNA into human lung, gastric and pancreatic cancer cells and analyzed the intracellular function of p51 in anti-oncogenesis in vitro and in vivo.


RESULTS
Overexpression of p51A revealed an anti-proliferative effect in vitro in all the cancer cells examined in this study. The anchorage-dependent and -independent cell growth of EBC1 cells carrying mutations in both p51 and p53 was suppressed and significant apoptosis following adenoviral transduction with p51 and/or p53 was seen. This growth suppression was cooperatively enhanced by the combined infection with adenoviral vectors encoding both p51 and p53. Furthermore, p51 activated several, but not all, p53-inducible genes, indicating that the mechanisms controlling p51- and p53-mediated tumor suppression differed.


CONCLUSIONS
Our observations indicate that, although p51 exhibited reduced anti-oncogenetic effects compared with p53, it cooperatively enhanced the anti-tumor effects of p53. Our results suggest that p51 functions as a tumor suppressor in human cancer cells in vitro and in vivo and may be useful as a potential tool for cancer gene therapy.
Kunisaki
Reiko
R
Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Ikawa
Shuntaro
S
Maeda
Toyoki
T
Nakazaki
Yukoh
Y
Kurita
Ryo
R
Harata
Masamitsu
M
Shutoh
Yukinobu
Y
Bai
Yuang Sung
YS
Soda
Yasushi
Y
Tanabe
Tsuyoshi
T
Dohi
Taeko
T
Kato
Rie
R
Ikawa
Yoji
Y
Asano
Shigetaka
S
Tani
Kenzaburo
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007763:Lac Operon; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins