The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines.

TLDR

In HPV‑positive cervical cancer cell lines, pRB is normal and p53 is low, suggesting functional alteration by HPV E7 and E6 oncoproteins. The study examined HPV‑positive and HPV‑negative cervical carcinoma cell lines for mutations in the p53 and retinoblastoma genes. Mutations were found in p53 (codons 273 and 245) and RB (splice‑junction deletions in exons 13 and 20) in the HPV‑negative C‑33A and HT‑3 lines, producing aberrant, non‑phosphorylated proteins that cannot bind E1A, supporting the idea that loss of pRB and p53 function—by mutation or HPV oncoprotein interaction—is a key step in cervical carcinogenesis.

Abstract

Human cervical carcinoma cell lines that were either positive or negative for human papillomavirus (HPV) DNA sequences were analyzed for evidence of mutation of the p53 and retinoblastoma genes. Each of five HPV-positive cervical cancer cell lines expressed normal pRB and low levels of wild-type p53 proteins, which are presumed to be altered in function as a consequence of association with HPV E7 and E6 oncoproteins, respectively. In contrast, mutations were identified in the p53 and RB genes expressed in the C-33A and HT-3 cervical cancer cell lines, which lack HPV DNA sequences. Mutations in the p53 genes mapped to codon 273 and codon 245 in the C33-A and HT-3 cell lines, respectively, located in the highly conserved regions of p53, where mutations appear in a variety of human cancers. Mutations in RB occurred at splice junctions, resulting in in-frame deletions, affecting exons 13 and 20 in the HT-3 and C-33A cell lines, respectively. These mutations resulted in aberrant proteins that were not phosphorylated and were unable to complex with the adenovirus E1A oncoprotein. These results support the hypothesis that the inactivation of the normal functions of the tumor-suppressor proteins pRB and p53 are important steps in human cervical carcinogenesis, either by mutation or from complex formation with the HPV E6 and E7 oncoproteins.