The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression.
The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53β and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53β, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.
Université de Toulouse, UPS, TRADGENE, Laboratory of Translational Control and Gene Therapy of Vascular Diseases, EA4554, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.
H
H
Bernard
B
B
Garmy-Susini
N
N
Ainaoui
L
L
Van Den Berghe
A
A
Peurichard
S
S
Javerzat
A
A
Bikfalvi
D P
DP
Lane
J C
JC
Bourdon
A-C
AC
Prats
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000098:blood supply* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D042501:Angiogenic Proteins; D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53