The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis.
ID4 (inhibitor of DNA binding 4) is a member of a family of proteins that function as dominant-negative regulators of basic helix-loop-helix transcription factors. Growing evidence links ID proteins to cell proliferation, differentiation and tumorigenesis. Here we identify ID4 as a transcriptional target of gain-of-function p53 mutants R175H, R273H and R280K. Depletion of mutant p53 protein severely impairs ID4 expression in proliferating tumor cells. The protein complex mutant p53-E2F1 assembles on specific regions of the ID4 promoter and positively controls ID4 expression. The ID4 protein binds to and stabilizes mRNAs encoding pro-angiogenic factors IL8 and GRO-alpha. This results in the increase of the angiogenic potential of cancer cells expressing mutant p53. These findings highlight the transcriptional axis mutant p53, E2F1 and ID4 as a still undefined molecular mechanism contributing to tumor neo-angiogenesis.
Fontemaggi
Giulia
G
Translational Oncogenomics Unit, Regina Elena Cancer Institute, Rome, Italy.
Dell'Orso
Stefania
S
Trisciuoglio
Daniela
D
Shay
Tal
T
Melucci
Elisa
E
Fazi
Francesco
F
Terrenato
Irene
I
Mottolese
Marcella
M
Muti
Paola
P
Domany
Eytan
E
Del Bufalo
Donatella
D
Strano
Sabrina
S
Blandino
Giovanni
G
D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008833:Microcirculation; D009154:Mutation; D009389:Neovascularization, Pathologic; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016207:Cytokines; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D016209:Interleukin-8; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A