Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells

Franklin, Renty B.; Ma, Jianfei; Zou, Jing; Guan, Zhixin; Kukoyi, Boone; Feng, Peng; Costello, Leslie C.

doi:10.1016/s0162-0134(03)00249-6

Cited by 153 publications

(116 citation statements)

References 16 publications

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“…This observation, combined with the ability of these proteins to confer zinc-specific uptake activity in vitro, suggested that Zip1 and Zip3 are involved in providing zinc to a variety of cell types. Consistent with this hypothesis, inhibiting expression of hZip1 in K562 and PC-3 cells using antisense RNA dramatically reduced zinc uptake activity (18,28). These results suggested that Zip1 is the major zinc uptake transporter in these cells.…”

Section: Figsupporting

confidence: 62%

Zinc-stimulated Endocytosis Controls Activity of the Mouse ZIP1 and ZIP3 Zinc Uptake Transporters

Wang

Dufner-Beattie

Kim

et al. 2004

Journal of Biological Chemistry

127

110

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The mouse mZip1 and mZip3 zinc transporters have been implicated in zinc acquisition by the cells of many tissues. This hypothesis raised the question of whether activity of these proteins is regulated to maintain zinc homeostasis. Neither mZIP1 nor mZIP3 mRNA levels are highly regulated by zinc status. Therefore, we investigated whether zinc controls the activity of these proteins post-translationally by altering their subcellular distribution. When expressed in transfected cells grown in zinc-replete medium, both mZip1 and mZip3 were largely present in intracellular organelles. However, these proteins were found to rapidly transit between the plasma membrane and intracellular compartments in zinc-replete cells. Zinc deficiency increased plasma membrane levels of mZip1 and mZip3 by decreasing their rates of endocytosis. Greater zinc deficiency was required to alter mZip3 distribution than was needed to affect mZip1. Increased surface levels correlated with increased zinc uptake activity. Taken together, these results suggest that post-translational control of mZip1 and mZip3 localization plays a role in zinc homeostasis. Moreover, our results indicate that zinc-responsive endocytosis is a conserved mechanism controlling activity of many mammalian zinc uptake transporters.

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Section: Figsupporting

confidence: 62%

Zinc-stimulated Endocytosis Controls Activity of the Mouse ZIP1 and ZIP3 Zinc Uptake Transporters

Wang

Dufner-Beattie

Kim

et al. 2004

Journal of Biological Chemistry

127

110

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“…It is now established that the zinc transporter, ZIP1, is responsible for zinc uptake and accumulation in prostate cells [11,12]. Recent studies using prostate tissue sections have revealed the expression of ZIP1 and high cellular zinc levels in citrate-producing non-malignant prostate glands [13].…”

Section: Zinc Transport and Metabolic Relationships In Prostate Cellumentioning

confidence: 99%

“…In contrast, adjacent malignant glands exhibited down-regulation of ZIP1 gene expression and transporter protein level and depletion of zinc. It is also significant that malignant prostate cell lines derived from metastatic sites (PC-3, LNCaP Du-145) exhibit Zip1 expression and zinc transporter activity [12]. This indicates that ZIP1 down-regulation in the primary site malignant cells in situ is not due to gene deletion or due to a fatal mutation.…”

Section: Zinc Transport and Metabolic Relationships In Prostate Cellumentioning

confidence: 99%

Zinc as an anti-tumor agent in prostate cancer and in other cancers

Franklin¹,

Costello²

2007

Archives of Biochemistry and Biophysics

211

142

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Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors. KeywordsZinc; prostate cancer; tumor suppressor; apoptosis; Krebs cycle; zinc transporter; intermediary metabolismThe physiology and biochemistry of zinc and its importance in normal cellular and bodily function has been the subject of numerous reviews [1][2][3][4]. The regulation and maintenance of a "normal" concentration and distribution of cellular zinc are essential to the function, metabolism, growth, proliferation and survival of cells. A significant clinical aspect of zinc is its role in the development and progression of malignancy. There is now compelling clinical and experimental evidence that zinc is an important factor in prostate cancer, and also in other types of cancer. In relation to essential tumor cell activities, the effects of zinc can be categorized as: intermediary metabolism and bioenergetics effects; motility and invasive effects; growth and proliferation effects. The actions of zinc on all three activities impose antitumor effects in malignant prostate cells and other tumor cells. This review will present the *Correspondence to: Renty B.

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“…On the other hand, the ZIP members are essential for an increase of the cytoplasmic zinc concentrations by enhancement of zinc uptake or release of stored zinc from subcellular compartments to the cytoplasm of the cell when zinc is deficient (6). Indeed, yeast ZRT1 and ZRT2 as well as mammalian ZIP1-5 proteins have been demonstrated to function in zinc uptake (7)(8)(9)(10)(11)(12)(13)(14)(15). Although a yeast zinc transporter, ZRT3, was reported to mediate the release of the intracellular compartmentalized zinc into the cytoplasm of the yeast cell (16), the mammalian counterpart is still not known.…”

mentioning

confidence: 99%

The ZIP7 Gene (Slc39a7) Encodes a Zinc Transporter Involved in Zinc Homeostasis of the Golgi Apparatus

Huang

Kirschke

Zhang

et al. 2005

Journal of Biological Chemistry

191

137

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It has been suggested that ZIP7 (Ke4, Slc39a7) belongs to the ZIP family of zinc transporters. Transient expression of the V5-tagged human ZIP7 fusion protein in CHO cells led to elevation of the cytoplasmic zinc level. However, the precise function of ZIP7 in cellular zinc homeostasis is not clear. Here we report that the ZIP7 gene is ubiquitously expressed in human and mouse tissues. The endogenous ZIP7 was associated with the Golgi apparatus and was capable of transporting zinc from the Golgi apparatus into the cytoplasm of the cell. Moreover, by using the yeast mutant strain ⌬zrt3 that was defective in release of stored zinc from vacuoles, we found that ZIP7 was able to decrease the level of accumulated zinc and in the meantime to increase the nuclear/cytoplasmic labile zinc level in the ZIP7-expressing zrt3 mutant. We showed that the protein expression of ZIP7 was repressed under zinc-rich condition, whereas there were no effects of zinc on ZIP7 gene expression and intracellular localization. Neither did zinc deficiency affect the intracellular distribution of ZIP7 in mammalian cells. Our study demonstrates that ZIP7 is a functional zinc transporter that acts by transporting zinc from the Golgi apparatus to the cytoplasm of the cell.

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Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells

Cited by 153 publications

References 16 publications

Zinc-stimulated Endocytosis Controls Activity of the Mouse ZIP1 and ZIP3 Zinc Uptake Transporters

Zinc-stimulated Endocytosis Controls Activity of the Mouse ZIP1 and ZIP3 Zinc Uptake Transporters

Zinc as an anti-tumor agent in prostate cancer and in other cancers

The ZIP7 Gene (Slc39a7) Encodes a Zinc Transporter Involved in Zinc Homeostasis of the Golgi Apparatus

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