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Zinc Deficiency Induced Cell Death as a Consequence of Cell Cycle Inhibition and Inactivation of Cell Survival Pathways
Author(s) -
Niles Brad J.,
Hanna Lynn A.,
Momma Tony Y.,
Clegg Michael S.,
Keen Carl L.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a996
Subject(s) - protein kinase b , phosphorylation , microbiology and biotechnology , programmed cell death , cell cycle , cell growth , biology , kinase , apoptosis , chemistry , tyrosine phosphorylation , biochemistry
Zinc (Zn) deficiency is characterized by apoptotic cell death, which may result from attenuated growth factor signaling. Growth factors such as IGF‐1 bind to receptor tyrosine kinases, leading to the activation of the serine/threonine kinase AKT. AKT phosphorylates a number of proteins involved in cell cycle control (e.g. p27 kip1 ) and apoptosis (e.g. BAD), regulating their turnover or cellular compartmentalization. To investigate the role of AKT in Zn deficiency‐induced apoptosis, 3T3 cells were cultured in Zn depleted (‐Zn; 0.5 μM Zn) or Zn supplemented (+Zn; 50 μM Zn) medium. By 8 hours, cellular Zn levels were decreased in the –Zn group compared to the +Zn group. After 16 hours, AKT phosphorylation levels were decreased in the –Zn group, which strongly correlated with up‐regulation of p27 kip1 , cell cycle inhibition, and a reduction in cell number. Subsequent to the dephosphorylation of AKT, pro‐apopototic proteins BAD and BAX were found enriched in the mitochondria, which was closely followed by caspase‐3 activation. Treatment of –Zn cells with IGF‐1 and Zn pyrithione induced the constitutive phosphorylation of AKT, while IGF‐1 treatment alone resulted in only transiently phosphorylated AKT. Transfection of –Zn cells with a plasmid vector encoding a constitutively active AKT resulted in decreased p27 kip1 levels and a 75% increase in cell number relative to mock transfected –Zn cells. This data strongly implicates reduced AKT phosphorylation as a contributing mechanism underlying Zn deficiency induced cell death. (NIH HD01743)