PMID:18305109

Citation	Wang, C, Li, N, Liu, X, Zheng, Y and Cao, X (2008) A novel endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest via p27 stabilization. J. Biol. Chem. 283:11565-74
Abstract	Calcium/calmodulin-dependent protein kinase II (CaMKII) regulates numerous physiological functions. Inhibition of CaMKII activity, mostly by synthetic reagents, has been proved to suppress cell growth in many cases. So far there are no reports about the physiological functions and underlying mechanisms of endogenous CaMKII inhibitory proteins in cell cycle progression. Here we report the characterization of a novel human endogenous CaMKII inhibitor, human CaMKII inhibitory protein alpha (hCaMKIINalpha), which directly interacts with activated CaMKII and effectively inhibits CaMKII activity. hCaMKIINalpha expression is negatively correlated with the severity of human colon adenocarcinoma. Overexpression of hCaMKIINalpha inhibits colon adenocarcinoma growth in vitro and in vivo by arresting the cell cycle at the S phase through its conserved inhibitory region (27CIR), whereas silencing the hCaMKIINalpha expression accelerates tumor growth and cell cycle progression. We found that the effect of hCaMKIINalpha on cell cycle is correlated with up-regulation of p27 expression, which may be due to the inhibition of proteasome degradation, but not transcriptional regulation, of p27. Moreover, hCaMKIINalpha deactivated MEK/ERK, which is prerequisite to the inhibition of Thr-187 phosphorylation and subsequent proteasomal degradation of p27, causing the inhibition of S-phase progression of cell cycle. The findings underscore a link between hCaMKIINalpha-mediated inhibition of CaMKII activity and p27-dependent pathways in controlling tumor cell growth and cell cycle and imply a potential application of hCaMKIINalpha in the therapeutics of colon cancers.
Links	PubMed PMC2431061 Online version:10.1074/jbc.M800436200
Keywords	Adenocarcinoma/metabolism; Amino Acid Sequence; Calcium-Calmodulin-Dependent Protein Kinase Type 2/chemistry; Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms/metabolism; Cyclin-Dependent Kinase Inhibitor p27/physiology; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Molecular Sequence Data; Neoplasms/metabolism; Phosphorylation; Proteins/chemistry; Proteins/physiology; Sequence Homology, Amino Acid; Tissue Distribution
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MP2K1	involved_in	GO:0070371: ERK1 and ERK2 cascade	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MP2K1	enables	GO:0004674: protein serine/threonine kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F	has_direct_input:(UniProtKB:P46527)	Seeded From UniProt	complete
HUMAN:MP2K1	involved_in	GO:0018107: peptidyl-threonine phosphorylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_direct_input:(UniProtKB:P46527)	Seeded From UniProt	complete
HUMAN:KCC2A	enables	GO:0004683: calmodulin-dependent protein kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:KCC2A	enables	GO:0009931: calcium-dependent protein serine/threonine kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:KCC2A	involved_in	GO:0006468: protein phosphorylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:CDK2	part_of	GO:0097135: cyclin E2-CDK2 complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:CDK2	part_of	GO:0097134: cyclin E1-CDK2 complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:CDK2	part_of	GO:0097123: cyclin A1-CDK2 complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.