Abstract
Zinc deficiency has been linked to human diseases, including cancer. MDMX, a crucial zinc-containing negative regulator of p53, has been found to be amplified or overexpressed in various cancers and implicated in the cancer initiation and progression. We report here that zinc depletion by the ion chelator TPEN or Chelex resin results in MDMX protein degradation in a ubiquitination-independent and 20S proteasome-dependent manner. Restoration of zinc led to recovery of cellular levels of MDMX. Further, TPEN treatment inhibits growth of the MCF-7 breast cancer cell line, which is partially rescued by overexpression of MDMX. Moreover, in a mass-spectrometry-based proteomics analysis, we identified TRPM7, a zinc-permeable ion channel, as a novel MDMX-interacting protein. TRPM7 stabilizes and induces the appearance of faster migrating species of MDMX on SDS-PAGE. Depletion of TRPM7 attenuates, while TRPM7 overexpression facilitates, the recovery of MDMX levels upon adding back zinc to TPEN-treated cells. Importantly, we found that TRPM7 inhibition, like TPEN treatment, decreases breast cancer cell MCF-7 proliferation and migration. The inhibitory effect on cell migration upon TRPM7 inhibition is also partially rescued by overexpression of MDMX. Together, our data indicate that TRPM7 regulates cellular levels of MDMX in part by modulating the intracellular Zn2+ concentration to promote tumorigenesis.
Highlights
P53, a zinc-containing transcription factor, is the most frequently mutated tumor suppressor protein in human cancer [4]
We found that the levels of ectopically expressed MDMX proteins in HEK293T cells decrease upon TPEN treatment (Fig. 1F)
We found that TPEN retained the ability to induce MDMX degradation even though the basal levels of MDMX increased in siRNA pool targeting Rpn1 (siRpn1) and siRpn2-2 transfected cells (Fig. 3, C and D)
Summary
Pangilinan, Asha Thuraisamy, Harman Chopra, Susumu Rokudai , Yong Yu1, Carol L. Yan Zhu1,* From the 1Department of Biological Sciences, St John’s University, Queens, New York, USA; 2Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan; 3Department of Biological Sciences, Columbia University, New York, New York, USA
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