Abstract
Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of mitosis, confirming the requirement for zinc influx as a trigger of mitosis. The zinc that influxes into cells to trigger mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the mitosis process compared to other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as cancer.
Highlights
Zinc is essential for life [1] and as such has indispensable roles in most biological systems
There is the formation of a zinc-dependant mitotic complex consisting of ZIP6, ZIP10, pS727STAT3 and p S38Stathmin that feeds into known mitotic pathways such as Stathmin-dependant microtubule reorganisation and HistoneH3-mediated chromosome condensation
STAT3 serves as a transcription factor (Fig. 8, stage 1) driving the gene expression of ZIP6 and ZIP10 [49] [23], which forms a heteromer with ZIP10 in the endoplasmic reticulum [29]
Summary
Zinc is essential for life [1] and as such has indispensable roles in most biological systems. Zinc plays a vital role in processes that are essential for cell survival, including signal transduction, gene expression, meiosis [3], immune functions [4], control of apoptosis, and cell cycle progression [5]. Zinc is vital during different cell cycle stages [6,7,8] as well as indispensable for passage through G2/M [8], suggestive of a regulatory role for zinc in mitotic entry. Nocodazole pS10HistoneH3 GAPDH ZIP6-SC 68kDa GAPDH ZIP6-Y 68kDa GAPDH ZIP10B 105kDa GAPDH ZIP10S 60kDa. Zinc has been known for over 40 years to be crucial for cell division, as established by demonstration of a zinc-dependent step in the G2 stage of the cell cycle [9] and how zinc was essential for progression from G2 to mitosis [10], confirming the ability of zinc to reverse a divalent cation chelating agent induced suppression of cell cycle progression [11], the exact molecular mechanism is still unknown.
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