p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis.
Intact p73 function is shown to be an important determinant of cellular sensitivity to anticancer agents. Inhibition of p73 function by dominant-negative proteins or by mutant p53 abrogates apoptosis and cytotoxicity induced by these agents. A polymorphism encoding either arginine (72R) or proline (72P) at codon 72 of p53 influences inhibition of p73 by a range of p53 mutants identified in squamous cancers. Clinical response following cisplatin-based chemo-radiotherapy for advanced head and neck cancer is influenced by this polymorphism, cancers expressing 72R mutants having lower response rates than those expressing 72P mutants. Polymorphism in p53 may influence individual responsiveness to cancer therapy.
Ludwig Institute for Cancer Research, Imperial College Faculty of Medicine, St. Mary's Campus, London, England.
Daniele
D
Bergamaschi
Milena
M
Gasco
Louise
L
Hiller
Alexandra
A
Sullivan
Nelofer
N
Syed
Giuseppe
G
Trigiante
Isik
I
Yulug
Marco
M
Merlano
Gianmauro
G
Numico
Alberto
A
Comino
Marlene
M
Attard
Olivier
O
Reelfs
Barry
B
Gusterson
Alexandra K
AK
Bell
Victoria
V
Heath
Mahvash
M
Tavassoli
Paul J
PJ
Farrell
Paul
P
Smith
Xin
X
Lu
Tim
T
Crook
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004358:Drug Therapy; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D010957:Plasmids; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins