Oxidative and calcium stress regulate DSCR1 (Adapt78/MCIP1) protein.
DSCR1 (adapt78) is a stress-inducible gene and cytoprotectant. Its protein product, DSCR1 (Adapt78), also referred to as MCIP1, inhibits intracellular calcineurin, a phosphatase that mediates many cellular responses to calcium. Exposure of human U251 and HeLa cells to hydrogen peroxide led to a rapid hyperphosphorylation of DSCR1 (Adapt78). Inhibitor and agonist studies revealed that a broad range of kinases were not responsible for DSCR1 (Adapt78) hyperphosphorylation, including ERK1/2, although parallel activation of the latter was observed. Phosphorylation of both DSCR1 (Adapt78) and ERK1/2 was attenuated by inhibitors of tyrosine phosphatase, suggesting the common upstream involvement of tyrosine dephosphorylation. The hyperphosphorylation electrophoretic shift in DSCR1 (Adapt78) mobility was also observed with other oxidizing agents (peroxynitrite and menadione) but not nonoxidants. Calcium ionophores strongly induced the levels of both hypo- and hyper-phosphorylated DSCR1 (Adapt78) but did not alter phosphorylation status. Calcium-dependent growth factor- and angiotensin II-stimulation also induced both DSCR1 (Adapt78) species. Phosphorylation of either or both serines in a 13-amino acid peptide made to a calcineurin-interacting conserved region of DSCR1 (Adapt78) attenuated inhibition of calcineurin. These data indicate that DSCR1 (Adapt78) protein is a novel, early stage oxidative stress-activated phosphorylation target and newly identified calcium-inducible protein, and suggest that these response mechanisms may contribute to the known cytoprotective and calcineurin-inhibitory activities of DSCR1 (Adapt78).
Lin
H Y
HY
The Research Service, Stratton Veterans Affairs Medical Center, the Ordway Research Institute and the Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA.
Michtalik
Henry J
HJ
Zhang
ShenLi
S
Andersen
Thomas T
TT
Van Riper
Dee A
DA
Davies
Kelvin K J A
KK
Ermak
Gennady
G
Petti
Lisa M
LM
Nachod
Schuyler
S
Narayan
Ananth V
AV
Bhatt
Nishant
N
Crawford
Dana R
DR
D000804:Angiotensin II / Q000378:metabolism; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001254:Astrocytoma / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006133:Growth Substances / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D024483:Vitamin K 3 / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006133:Growth Substances; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D009124:Muscle Proteins; D016877:Oxidants; C108612:RCAN1 protein, human; D000804:Angiotensin II; D030421:Peroxynitrous Acid; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; D017027:Protein Tyrosine Phosphatases; D002118:Calcium