P21: a monitor of p53 dysfunction in ovarian neoplasia

Abstract

p53 is an important tumor suppressor gene which is activated in response to DNA damage. The induced expression of p53 causes either cell cycle G1 arrest or apoptosis. The recently cloned p21 gene (WAF1/CIP1/SDI1) is known to be directly activated by wild-type but not mutant p53 and can suppress the growth of human cells in G1 by inhibiting the activity of cyclin-dependent kinases (CDKs). As p21 is activated by p53 and is a negative regulator of the cell cycle, it is possible that p21 could be a sensitive marker to monitor p53 function. To investigate the mRNA expression level and mutation status of p53 and p21 genes, quantitative polymerase chain reaction (PCR) and direct cDNA sequence analysis were performed. mRNA expression levels of p53 and p21 genes relative to the β-tubulin gene were examined in 32 ovarian tumors (24 carcinomas, six low malignant potentials (LMPs), two benigns) and six normal ovaries. Of 13 ovarian tumors with p21 underexpression, nine p53 mutated cases (69%) and one polymorphism case were found. Among nine p53 mutated cases, three cases showed p53 overexpression, another three cases showed p53 underexpression and a further three cases showed normal expression of p53. These findings suggest that mRNA underexpression of p21 may be a more useful indicator of p53 dysfunction than mRNA expression of p53.