Differential Regulation of Estrogen Receptor α Turnover and Transactivation by Mdm2 and Stress-Inducing Agents

Abstract

In mammalian cells, the level of estrogen receptor A (ERA) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitinligase directly interacts with ERA in a ternary complex with p53 and is involved in the regulation of ERA turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ERA and abolished its 17B-estradioldependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ERA stability and transcriptional activity in human cancer cells. [Cancer Res 2007;67(11):5513-21]

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

“…Among candidates whose siRNA-mediated depletion stabilizes HPIP, MDM2 was selected for further investigation given the previously established link between MDM2 and estrogen signaling (Figure 5a). 34 We confirmed that HPIP is indeed stabilized in the parental MCF7 cells infected with five distinct MDM2 shRNA lentiviral constructs (Figure 5b). HPIP and MDM2 protein levels were also inversely correlated in p53-depleted cells, indicating that MDM2 negatively regulates HPIP levels in a p53-independent manner.…”

“…Therefore, MDM2 promotes E2-dependent AKT activation in p53-depleted breast cancer cells and is also involved in ERa turnover, as previously suggested. 34 Importantly, MDM2 depletion in p53-deficient MCF7 cells strongly sensitized them to tamoxifen, most likely as a result of defective AKT activation (Figure 7c). Although E2 stimulation triggered cell proliferation in p53-depleted MCF7 cells, as judged by the accumulation of cells in the S phase (from 11.1% in unstimulated cells to 23.7%), MDM2 deficiency severely impaired cell proliferation in both unstimulated and E2-treated cells (5.5% and 9.2%, respectively, see Figure 7d).…”

P53 Arg72Pro and MDM2 SNP309 Polymorphisms Cooperate to Increase Lung Adenocarcinoma Risk in Chinese Female Non-smokers: A Case Control Study

“…This phenomenon may be linked to (1) previous reports that the MDM2 GG genotype leads to high MDM2 protein expression (Bond et al,2004) and (2) the ability of MDM2 to negatively regulate estrogen receptor (ER) expression (Duong et al, 2007) because the estrogen signaling pathway is thought to be associated with an increased risk of developing lung cancer, especially adenocarcinoma (Karlsson et al, 2012). In addition, polycyclic aromatic hydrocarbons, which are important component of both cooking oil fumes and cigarette smoke, are reported to decrease estrogen levels (Siegfried, 2010).…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…2). Mdm2 can physically interact with ligand-binding domain of ERα regardless of the presence of estrogen and can directly enhance ERα ubiquitination in vivo [160]. Mdm2 oncogenic ubiquitin-ligase directly interacts with ERα in a ternary complex with p53 and is involved in the regulation of ERα turnover (both in the absence or presence of estrogens).…”