Cytoplasmic mutant p53 increases Bcl-2 expression in estrogen receptor-positive breast cancer cells

Abstract

The Bcl-2 gene is positively regulated by estrogen (E2) primarily through E2-response elements in the coding region and a putative p53 negative regulatory element (NRE) containing a short upstream open reading frame (uORF). The ability of mutant p53 to repress or induce Bcl-2 expression is controversial. In this study E2-receptor positive (ER(+))/wild-type p53 MCF-7cells were transfected with p53Delta291, which lacks a nuclear localization signal or a DNA binding domain mutant, p53(173L). Both p53 mutants but especially p53Delta291 increased Bcl-2 protein expression from a CMV-NRE-Bcl-2 cDNA construct in an NRE-position/orientation independent manner as well as from a 1.7 kb Bcl-2 promoter reporter gene. Bcl-2 protein expression prevented the p53Delta291-mediated increase in Bcl-2 promoter activity although immunoprecipitation demonstrated that only a small proportion of the wild-type p53 but not p53Delta91 protein interacts with Bcl-2. Unless levels of ectopically expressed mutant p53 were extremely high, stable expression of mutant p53 in MCF-7 cells moderately increased Bcl-2 protein levels. Expression of mutant p53 did not alter E2 regulation of Bcl-2, however, mutation of the uORF prevented regulation by both mutant p53 and E2. Adenovirus-mediated overexpression of WT p53 strongly reduced Bcl-2 expression in ER(-)/mut p53 MDA-MB-231 cells. Taken together these data support the position that mutant p53 behaves in a dominant "positive" manner relieving repression by WT p53 or another Bcl-2 transcriptional inhibitor in a manner independent of nuclear translocation.

Antiproliferative effects of copper(II)–polypyridyl complexes in breast cancer cells through inducing apoptosis

“…One pathway is the deathreceptor pathway and the other is the mitochondrial pathway (Chandra et al 2002;Teijido and Dejean 2010); the latter has been regarded as an important mediator of cell apoptosis in mammals (Zhang et al 2010). In the mitochondrial pathway, Bcl-2 family members carried the responsibility for the regulation of apoptosis in different situations, including the antiapoptotic Bcl-2 protein and pro-apoptotic Bax protein (Pratt et al 2007). In this study, we considered the Bax/Bcl-2 ratio a crucial factor in determining the fate of cells toward apoptosis.…”

Role of the Crosstalk between Autophagy and Apoptosis in Cancer

“…Only wild-type p53 has been conclusively shown to trigger apoptosis; therefore, it is particularly important to consider that therapeutics targeted against the wild-type protein may be ineffective in cancer cells which contain mutant p53. For instance, one study has shown that in estrogen-positive breast cancer cells, expression of a truncated p53 lacking the C-terminal 102 amino acids increases BCL-2 expression by alleviating the repression by endogenous wild-type p53, thus decreasing apoptosis [129]. …”

The rebel angel: mutant p53 as the driving oncogene in breast cancer

“…Positive association in breast cancer has been found between mutant p53 and expression of the anti-apoptotic splice variant of Survivin (92). Mutant p53s have been also found to increase the levels of Bcl-2 (93). Recently, Bcl-2 has been described to be frequently overproduced in triple-negative breast cancers (TNBCs) and, in contrast to other mammary tumor types, to correlate with poor patient survival (94).…”