Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts.
Discrimination of oncogenic growth signals from normal growth signals is crucial for tumor suppression. The transcription factor E2F, the main target of pRB, plays central role in cell proliferation by activating growth-promoting genes. E2F also plays an important role in tumor suppression by activating growth-suppressive genes such as pro-apoptotic genes. The regulatory mechanism of the latter genes is not known in detail, especially in response to normal and oncogenic growth signals. E2F is physiologically activated by growth stimulation through phosphorylation of pRB. In contrast, upon dysfunction of pRB, a major oncogenic change, E2F is activated out of control by pRB, generating deregulated E2F activity. We show here that the tumor suppressor TAp73 gene, which can induce apoptosis independently of p53, responds to deregulated E2F activity, but not to physiological E2F activity induced by growth stimulation in human normal fibroblasts. We identified E2F-responsive elements (ERE73s) in TAp73 promoter that can specifically sense deregulated E2F activity. Moreover, RB1-deficient cancer cell lines harbored deregulated E2F activity that activated ERE73s and the TAp73 gene, which were suppressed by re-introduction of pRB. These results underscore the important role of deregulated E2F in activation of the TAp73 gene, a component of major intrinsic tumor suppressor pathways.
Department of Molecular Virology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Eiko
E
Ozono
Hideyuki
H
Komori
Ritsuko
R
Iwanaga
Tatsuya
T
Tanaka
Takahiro
T
Sakae
Hodaka
H
Kitamura
Shoji
S
Yamaoka
Kiyoshi
K
Ohtani
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D044967:Serum / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D003470:Culture Media; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D005047:Etoposide