Inactivation of the tumor suppressor p53 is central to carcinogenesis and acquisition of resistance to drug-induced apoptosis. The majority of alterations are missense mutations and occur within the DNA-binding domain. However, little is known about the point mutations in the tetramerization domain (TD). Here we investigated the properties of a new p53 mutant (Lys 351 to Asn) in the TD identified in a cisplatin-resistant ovarian carcinoma cell line (A2780 CIS). We found that K351N substitution significantly reduces the thermodynamic stability of p53 tetramers without affecting the overall half-life of the protein. Moreover, p53 K351N has a reduced ability to bind DNA and to trans-activate its specific target gene promoters, such as bax. Data obtained from the analysis of p53 subcellular localization revealed that K351N mutation inhibits the nuclear export of p53 and accumulation in the cytoplasm induced by cisplatin treatment. These results identify p53 K351N as a new cancer associated mutant with reduced tumor suppressor activity and altered functions in response to apoptotic stimuli. © 2009 Landes Bioscience.

Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain / Muscolini, Michela; Elisa, Montagni; Silvana, Caristi; Takao, Nomura; Rui, Kamada; Silvia Di, Agostino; Marco, Corazzari; Mauro, Piacentini; Giovanni, Blandino; Antonio, Costanzo; Kazuyasu, Sakaguchi; Tuosto, Loretta. - In: CELL CYCLE. - ISSN 1538-4101. - 8:20(2009), pp. 3396-3405. [10.4161/cc.8.20.9910]

Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain

MUSCOLINI, MICHELA;TUOSTO, Loretta
2009

Abstract

Inactivation of the tumor suppressor p53 is central to carcinogenesis and acquisition of resistance to drug-induced apoptosis. The majority of alterations are missense mutations and occur within the DNA-binding domain. However, little is known about the point mutations in the tetramerization domain (TD). Here we investigated the properties of a new p53 mutant (Lys 351 to Asn) in the TD identified in a cisplatin-resistant ovarian carcinoma cell line (A2780 CIS). We found that K351N substitution significantly reduces the thermodynamic stability of p53 tetramers without affecting the overall half-life of the protein. Moreover, p53 K351N has a reduced ability to bind DNA and to trans-activate its specific target gene promoters, such as bax. Data obtained from the analysis of p53 subcellular localization revealed that K351N mutation inhibits the nuclear export of p53 and accumulation in the cytoplasm induced by cisplatin treatment. These results identify p53 K351N as a new cancer associated mutant with reduced tumor suppressor activity and altered functions in response to apoptotic stimuli. © 2009 Landes Bioscience.
2009
apoptosis; chemotherapy resistance; p53; tumor suppressor
01 Pubblicazione su rivista::01a Articolo in rivista
Characterization of a new cancer-associated mutant of p53 with a missense mutation (K351N) in the tetramerization domain / Muscolini, Michela; Elisa, Montagni; Silvana, Caristi; Takao, Nomura; Rui, Kamada; Silvia Di, Agostino; Marco, Corazzari; Mauro, Piacentini; Giovanni, Blandino; Antonio, Costanzo; Kazuyasu, Sakaguchi; Tuosto, Loretta. - In: CELL CYCLE. - ISSN 1538-4101. - 8:20(2009), pp. 3396-3405. [10.4161/cc.8.20.9910]
File allegati a questo prodotto
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/360911
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 15
social impact