Allele specific gain-of-function activity of p53 mutants in lung cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• p53 mutations often result in stable mutant proteins with gain of function (GOF) oncogenic activity.
• These GOF mutant p53 proteins play a dominant role in cancer, distinct from simple loss of wild-type p53 function.

Purpose of the Study:

• To investigate the allele-specific gain of function (GOF) activities of different p53 mutants in human lung cancer.
• To determine the impact of GOF p53 mutants on cancer cell growth, tumorigenicity, and target gene transactivation.

Main Methods:

• Knock-down of mutant p53 in human lung cancer cell lines (ABC1, H1437) with distinct p53 mutations.
• Assessment of cell growth rates and tumorigenicity in nude mice.
• Transient transcriptional assays in p53-null H1299 cells to evaluate transactivation potential on p53 target gene promoters (Axl, p21).

Main Results:

• Knock-down of mutant p53 reduced growth rates in both ABC1 (p53-P278S) and H1437 (p53-R267P) cell lines.
• p53 knock-down reduced tumorigenicity for ABC1 cells but escalated it for H1437 cells.
• Mutant p53-P278S activated the Axl promoter but not the p21 promoter, while p53-R267P activated both Axl and p21 promoters, unlike wild-type p53.

Conclusions:

• GOF p53 mutations exhibit allele-specific behavior in lung cancer.
• The transactivation properties of GOF p53 mutants, particularly regarding p21 activation, are critical determinants of their oncogenic or tumor-suppressive roles.
• p21 activation appears important for tumor suppression mediated by p53.