Disease relevance of Ppp3ca

• On the contrary, overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) impairs CN activity both in transfected human neuroblastoma cell lines and in the motor cortex of brain from FALS-transgenic mice [1].
• We have monitored CN activity in cultured human neuroblastoma SH-SY5Y cells and obtained evidence that CN activity is promoted by treatment with ascorbate or dithiothreitol and impaired by oxidative stress [1].
• After 14 days, in CN mice, the LVIDd and LVMI were significantly increased, but sudden death had not occurred [2].
• We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice [3].
• Calcineurin (CN) is implicated as a key signaling molecule in hypertrophy [4].

High impact information on Ppp3ca

• CaM-BPs were expressed differentially, with B lymphocytes having four times more of the CN-like protein than T lymphocytes, while in thymocytes, a 65K polypeptide was the major CaM-BP [5].
• The mechanisms underlying the X-linked thymus-independent (B) lymphocyte functional defect in the CBA/N (CN) mice and their F1 progeny were studied [6].
• These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D [7].
• Moreover, when calcineurin signaling is compromised with cyclosporin A, muscles from OV wild-type mice display a lower molecular weight form of CnA, originally detected in failing hearts, whereas CnA* muscles are spared this manifestation [7].
• Here we show that skeletal muscles overexpressing an activated form of calcineurin (CnA*) exhibit a phenotype indistinguishable from wild-type counterparts under normal weightbearing conditions and respond to OV with a similar doubling in cell size and slow fiber number [7].

Chemical compound and disease context of Ppp3ca

• Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed [2].
• To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01) [3].

Biological context of Ppp3ca

• Inhibiting CnA with cyclosporin A (CsA) leads to nephron deficit in rat metanephric organ cultures and apoptosis in various renal cell lines [8].
• Consistent with these findings, human genetics studies in a large sample of affected families detected a significant association of the PPP3CC gene, which encodes the CN gamma catalytic subunit with schizophrenia [9].
• The cloning and characterization of cDNAs for the catalytic subunit of calcineurin (CN) from murine and human brain libraries were carried out using nonisotopic methods [10].
• In addition to alterations in development, there is an absence of proliferation and an increase of cell death in the NZ with loss of CnA-alpha [11].
• In summary, absence of CnA-alpha but not CnA-beta leads to a defect in normal maturation of the NZ and glomeruli, alterations in the cell cycle, and impaired kidney function [11].

Anatomical context of Ppp3ca

• These results indicate that CN is required for full iNOS expression and the effective activation of NF-kappaB in RAW 264.7 and peritoneal macrophages [12].
• Transient expression of constitutively active CN in mouse peritoneal macrophages and RAW 264.7 macrophages strongly activated NF-kappaB, a key mediator of iNOS expression [12].
• Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system [13].
• Consistent with this induction, we also observed that members of the dystrophin-associated protein (DAP) complex were present at the sarcolemma of mdx/CnA* mouse muscle [14].
• Muscles from mdx/CnA* displayed increased nuclear localization of NFATc1 and a fiber type shift towards a slower phenotype [14].

Associations of Ppp3ca with chemical compounds

• CnA is a serine/threonine phosphatase activated by intracellular calcium [8].
• Ca(2+) and Ca(2+)/calmodulin-dependent protein phosphatase calcineurin (CN) have been known to play crucial roles in immune response and inflammation [12].
• Using mouse peritoneal macrophages and RAW 264.7 macrophage cells, we demonstrated that LPS mobilized intracellular free Ca(2+) and induced CN phosphatase activity. iNOS expression and NO secretion in response to LPS were suppressed by Ca(2+) antagonists (TMB-8, BAPTA/AM, and nifedipine) and CN inhibitor (cyclosporin A) [12].
• The coding sequences of these two genes are distinguished by the absence (PP2B alpha 1) or the presence (PP2B alpha 2) of an amino terminus containing polyproline [15].
• The immunosuppressive drugs cyclosporin A and FK506 profoundly inhibit the calcium-dependent signaling pathway in T lymphocytes by interfering with the activity of the calcium/calmodulin (CaM)-dependent serine/threonine phosphatase, calcineurin (CN) [16].

Regulatory relationships of Ppp3ca

• Calcineurin (CN) is a serine/threonine-specific protein phosphatase activated by Ca(2+) and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes [17].

Other interactions of Ppp3ca

• Overexpression of dominant negative mutant of IKKalpha and -beta demonstrates that only IKKbeta is the target for CN [12].
• We also found that CN mediates NF-kappaB activation via IkappaB-alpha hyperphosphorylation and degradation [12].
• In the present study, we therefore crossed CnA* mice with mdx mice to determine the suitability of elevating calcineurin activity in preventing the dystrophic pathology [14].
• In this context, we previously showed that mice expressing enhanced muscle calcineurin activity (CnA*) displayed elevated levels of utrophin around their sarcolemma [14].
• In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity [18].

Analytical, diagnostic and therapeutic context of Ppp3ca

• In agreement with these results, Northern blots of mammalian brain RNA showed transcripts for both genes, with about two to three times more of the PP2B alpha 1 mRNAs, whereas in chicken and lizard, only PP2B alpha 1 transcripts were detected [15].
• Southern blot analysis showed unique restriction fragments for both genes in seven mammalian species; however, in organisms from two nonmammalian vertebrates (chicken and lizard), hybridization was observed only for PP2B alpha 1 [15].
• Finally, immunofluorescence experiments using Mac-1 antibodies showed a reduction in the number of infiltrating immune cells in muscles from mdx/CnA* mice [14].
• We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release [17].
• In our present study, extract of Fructus cannabis (EFC) with activation of CN, extracted from Chinese traditional medicine, was used to determine the effects on memory and immunity [19].

References