Cooperation between p53 and hMLH1 in a human colocarcinoma cell line in response to DNA damage

Faina Vikhanskaya, Gennaro Colella, Monica Valenti, Silvio Parodi, Maurizio D'Incalci, Massimo Broggini

Research output: Contribution to journalArticle

Abstract

We have studied the possible interactions between the mismatch repair system and p53 in a human colon cancer cell line, HCT-116 (known to have a homozygous mutation in mismatch repair gene hMLH1 on chromosome 3) and in a clone obtained after insertion of a single copy of chromosome 3 (HCT- 116+ch3). Loss of DNA mismatch repair activity resulted in resistance to cisplatin (DDP). p53 accumulated differently in these cell lines after treatment with DDP. Initially at similar high levels after DDP treatment, p53 maintained the increase in HCT-116 cells, even 72-96 h after drug exposure, whereas HCT-116+ch3 mismatch-proficient cell line p53 declined to basal levels after 48 h. The higher levels of p53 in mismatch-deficient HCT-116 cells were accompanied by increased transcriptional activity as assessed by the gel-retardation assay and by activation of a promoter containing a p53 DNA binding site. To better understand the role of p53, if any, in cell sensitivity to DDP, we disrupted p53 in both cell lines by stable transfection with the human papillomavirus type 16 E6 gene. HCT-116/E6 cells were more sensitive to DDP than the parental cell line, whereas HCT- 116+ch3/E6 were fairly similar to HCT-116+ch3 with normal p53 function. Although in our system the transfer of the entire chromosome 3 was used (thus not excluding a possible role of other genes localized on this chromosome), our data indicate that p53 can cooperate with the mismatch repair system. In fact, the lack of hLMH1, at least in these cells, enhances the role of p53 in protecting the cells from DDP-induced DNA damage.

Original languageEnglish
Pages (from-to)937-941
Number of pages5
JournalClinical Cancer Research
Volume5
Issue number4
Publication statusPublished - Apr 1999

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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