Alternative splicing of p53 and p73: the novel p53 splice variant p53delta is an independent prognostic marker in ovarian cancer.
Similar to p73, the tumor suppressor gene p53 is subject to alternative splicing. Besides p53DeltaE6 and p53beta, we identified p53zeta, p53delta and p53varepsilon, arising from alternative splicing of exon 6 and intron 9, respectively. p53 splice variants were present in 18 of 34 ovarian cancer cell lines (52.9%) and 134 of 245 primary ovarian cancers (54.7%). p53delta expression was associated with impaired response to primary platinum-based chemotherapy (P=0.032). Also, p53delta expression constituted an independent prognostic marker for recurrence-free and overall survival (hazard ratio 1.854, 95% confidence interval 1.121-3.065, P=0.016; and hazard ratio 1.937, 95% confidence interval 1.177-3.186, P=0.009, respectively). p53beta expression was associated with adverse clinicopathologic markers, that is, serous and poorly differentiated cancers (P=0.002 and P=0.008, respectively), and correlated with worse recurrence-free survival in patients exhibiting functionally active p53 (P=0.049). DeltaN'p73 constituted the main N-terminally truncated p73 isoform and was preferentially found in ovarian cancer cell lines showing functionally active p53, supporting our hypothesis that N-terminally truncated p73 isoforms can alleviate the selection pressure for p53 mutations by the inhibition of p53 protein function.
Hofstetter
G
G
Department of Gynecology and Obstetrics, Innsbruck Medical University, Innsbruck, Austria.
Berger
A
A
Fiegl
H
H
Slade
N
N
Zorić
A
A
Holzer
B
B
Schuster
E
E
Mobus
V J
VJ
Reimer
D
D
Daxenbichler
G
G
Marth
C
C
Zeimet
A G
AG
Concin
N
N
Zeillinger
R
R
D017398:Alternative Splicing; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007438:Introns; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins