TAp73/deltaNp73 ratios and chemosensitivity (CROSBI ID 539615)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa
Podaci o odgovornosti
Slade, Neda ; Zorić, Arijana ; Moll, Ute M. ; Pavelić, Jasminka
engleski
TAp73/deltaNp73 ratios and chemosensitivity
The p53 family member p73 generates transactivating forms (TAp73) as well as several N-terminally truncated, transactivation-deficient dominant-negative isoforms (collectively called ∆ TAp73). There are three such isoform proteins, called ∆ Np73, Ex2p73 and Ex2/3p73. ∆ Np73, derived from either the TA promoter (P1) or an alternative P2 promoter in Intron 3, is frequently overexpressed both on the RNA and protein level in a variety of human tumors. ∆ Np73 can inhibit TAp73 and wt p53 upon forced expression in cultured cells. TAp73 was reported to be activated by a variety of DNA damaging agents that also induce p53. Here we confirmed TAp73 upregulation upon cellular stress. Using quantitative real time PCR, we determined the endogenous expression of all known p73 N-terminal transcripts (TAp73, ∆ Np73, ∆ N'p73, Ex2del p73 and Ex2/3del p73) in p53-null H1299 and wt p53 harboring RKO cells after treatment with  -irradiation or several cytotoxic DNA damaging agents (cisplatin, doxorubicin, etoposide and camptothecin). Although somewhat dependent on the type of DNA damage, the most highly upregulated isoforms were TAp73 and Ex2/3del p73, while the putative oncogenic  Np73 was only slightly elevated. We confirmed our results at the protein level. However, no correlation between the isoform expression profile and cell survival was seen. Furthermore, to assess the contribution of ∆ Np73 to chemoresistance, we used a Hela-∆ Np73 tet-on inducible cell line that expresses high levels of the transgene upon tetracycline. After induction and subsequent treatment with several DNA damaging agents, ∆ Np73 protein expression was correlated with cell survival. Of note, DNA damage further upregulated ∆ Np73 protein, and this damage-mediated induction translated into increased chemoresistance. We conclude that the cellular TA/∆ Np73 ratios likely determine the outcome of the p73 response to cytotoxic stress.
p73; p53; DNA damage
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Podaci o prilogu
239-239.
2006.
objavljeno
Podaci o matičnoj publikaciji
13th Annual p53 Workshop
New York (NY): Columbia University Press
Podaci o skupu
13th Annual p53 Workshop
poster
20.05.2006-24.05.2006
Sjedinjene Američke Države