Abstract
Loss of p53’s proper function accounts for over half of identified human cancers. We identified the metal transporter ZIP14 (Zinc-regulated transporter (ZRT) and Iron-regulated transporter (IRT)-like Protein 14) as a p53-regulated protein. ZIP14 protein levels were upregulated by lack of p53 and downregulated by increased p53 expression. This regulation did not fully depend on the changes in ZIP14’s mRNA expression. Co-precipitation studies indicated that p53 interacts with ZIP14 and increases its ubiquitination and degradation. Moreover, knockdown of p53 resulted in higher non-transferrin-bound iron uptake, which was mediated by increased ZIP14 levels. Our study highlights a role for p53 in regulating nutrient metabolism and provides insight into how iron and possibly other metals such as zinc and manganese could be regulated in p53-inactivated tumor cells.
Highlights
Over 50% of identified human cancers are caused by mutations in the gene encoding tumor suppressor p53 [1,2,3,4]
In contrast to ZRT/IRT-like protein 14 (ZIP14), divalent metal-ion transporter 1 (DMT1) did not change when p53 (Figure 1G). These results suggest that the WT p53 plays a role in regulating ZIP14, but not DMT1 in expression was suppressed (Figure 1G)
Nutrient uptake and metabolism in tumor cells are controlled by genetic mutations and cellular responses to the tumor microenvironment
Summary
Over 50% of identified human cancers are caused by mutations in the gene encoding tumor suppressor p53 [1,2,3,4]. P53 has a well-documented function as a transcription factor [5]. It possesses transcription-independent cytosolic functions, including inhibition of autophagy [6,7,8,9], regulation of mitochondrial function [10,11] and regulation of apoptosis [12]. Inactivation of p53 contributes to cancer initiation and progression, and to chemotherapy resistance [13,14]. Proliferating cells need considerably more nutrients than normal cells. Elucidation of p53’s function in regulating nutrient transport is important to the understanding of how p53 influences tumor metabolism
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