Disease relevance of SRI

• We generated an adenovirus encoding the SOR coding DNA with a separate cassette for green fluorescent protein (GFP) both driven by the CMV-promoter to induce SOR-overexpression (Ad.SOR.GFP) [1].
• RESULTS: Sorcin gene expression was significantly higher in AL patients than in normal contrls (P < 0.001), and higher in relapsed/refractory acute myeloid leukemia (AML) patients than in those newly diagnosed or in complete remission [2].
• The translocation process takes place also in E. coli BL21 cells that express recombinant sorcin, r-sorcin, and can be exploited in the purification of the protein [3].
• Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells [4].
• Purification, cDNA cloning, and expression of human sorcin in vincristine-resistant HOB1 lymphoma cell lines [5].

Psychiatry related information on SRI

• Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study [6].
• Digit symbol substitution (DSS), simulated driving reaction time (SDRT), choice reaction time (CRT) and self assessment of impairment (SRI) were measured simultaneously with Est.BAC [7].
• To determine whether tobacco dependence exhibits multidimensional properties, we examined two existing, independent data sets, one from SRI International (n=443) and another from the University of Michigan (n=445) [8].
• Paroxetine is the SRI most extensively studied in Social Anxiety Disorder with positive therapeutic results [9].
• Furthermore, the E4 isoform of the 22 kDa fragment is significantly more toxic than the same fragment derived from the E3 isoform, suggesting the possibility of a direct role of apoE-associated neurotoxicity in the pathophysiology of Alzheimer's disease [10].

High impact information on SRI

• In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22) [11].
• Taspase1 proenzyme is intramolecularly proteolyzed generating an active 28 kDa alpha/22 kDa beta heterodimer [12].
• We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats [13].
• Western blotting of isolated mitochondria from HBP-treated endothelial cells showed that HBP is present in 2 forms - 28 and 22 kDa [14].
• Modulation of intracellular Ca2+ levels in the heart by sorcin and FKBP12, two accessory proteins of ryanodine receptors [15].

Chemical compound and disease context of SRI

• Immunocytochemical identification and localization of the Mr 22,000 calcium-binding protein (sorcin) in an adriamycin-resistant myelogenous leukemia cell line [16].
• Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients [17].
• Pharmacokinetic parameters after a single oral dose of aprepitant 240 mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73 m(2)]) and 16 healthy and age-, sex- and weight-matched subjects (controls) [17].
• Administration of SRI 3961 found this compound 8000 times more potent than all-trans-retinoic acid, while SRI 7167-67 failed to show any evidence for developmental toxicity even after exposure to 105 mg/kg [18].
• Use of an SRI threshold of less than .55 resulted in ultrasound being as accurate as captopril renography in predicting an angiographically documented stenosis of greater than or equal to 50% [19].

Biological context of SRI

• Here we show that the human homolog of the hamster sorcin gene resides on chromosome 7 like the P-glycoprotein-encoding genes [20].
• 4. Overlay assays using deletion constructs of the synexin N-terminal domain mapped the sorcin binding site to the N-terminal 31 amino acids of the synexin protein [21].
• These results strengthen the notion that overexpression of SOR improves cardiac contractility independent of beta-adrenergic stimulation and may prove beneficial in the treatment of decreased cardiac output such as heart failure [1].
• Overexpression of sorcin protein by gene transfection in K562 cells resulted in increased drug resistance, from 4.1- to 22.5-fold, to a variety of chemotherapeutic agents, including doxorubicin, etoposide, homoharringtonine and vincristine [22].
• In this report, we have carried out experiments to dissect out the contribution of sorcin by itself to drug resistant phenotype in K562 cells [22].

Anatomical context of SRI

• The association of endogenous sorcin and PS2 was demonstrated in cultured cells and human brain tissues [23].
• The antibody immunoprecipitated a 22-kDa protein as well as the 30-kDa protein from the lysate of Jurkat cells [24].
• Additionally, synexin forms a complex with sorcin and recruits this protein to chromaffin granule membranes in a Ca2+-dependent manner [21].
• In addition, sorcin and grancalcin can be co-immunoprecipitated from lysates of human umbilical vein endothelial cells [25].
• A 1.7-fold increase of the SOR protein amount in cultured myocytes treated with Ad.SOR.GFP compared to Ad.GFP-transfected cells indicated a successful overexpression of SOR [1].

Associations of SRI with chemical compounds

• Systematic testing of the heterodimerization abilities of the PEF proteins using the yeast two-hybrid and glutathione S-transferase pull-down assays revealed the new finding that grancalcin interacts strongly with sorcin [25].
• We previously observed by gene profiling that sorcin is significantly up-regulated in a doxorubicin-induced MDR leukemia cell line, K562/A02, over its parent cells [22].
• In contrast to the parental host fibroblasts, sorcin transfectants displayed a rapid and transient rise in intracellular calcium in response to caffeine, suggesting organization of the accumulated ryanodine receptor protein into functional calcium release channels [26].
• Calcium binding to purified r-sorcin occurs at micromolar concentrations of the metal and is accompanied by a conformational change that renders the protein soluble in the non-ionic detergent Triton X-114 [3].
• L1210 sublines independently selected for resistance to teniposide (VM-26), etoposide (VP-16), doxorubicin (DOX), dactinomycin (DACT), or vincristine (VCR) express an anionic, 22-kDa protein that is not observed in extracts of parental L1210 cells [27].

Physical interactions of SRI

• Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor [23].
• Recombinant sorcin bound to cardiac and skeletal HIS6-tagged alpha1 C termini immobilized on Ni2+ resin [28].
• Mutational analysis reveals that the C-terminal sequence of GLYT1 (-SRI) is necessary for the transporter to interact with the PDZ domains I and II of PSD-95 [29].
• When present in dimyristoyl phosphatidylcholine (DMPC) complexes, the 22-kDa amino-terminal fragments (residues 1;-191) of apoE3 and apoE4 bound to the LDLR with approximately 100-fold greater affinity than the 22-kDa fragment of apoE2 [30].
• Salmon serum 22 kDa insulin-like growth factor-binding protein (IGFBP) is IGFBP-1 [31].

Enzymatic interactions of SRI

• In vitro, purified PR3 cleaved procaspase-3 into an active 22-kDa fragment [32].

Regulatory relationships of SRI

• The EGF-stimulated phosphorylation of the brain 22-kDa protein requires its reconstitution into phospholipid vesicles [33].
• The magnitude of inhibition of PLD activity was correlated well with the extent of toxin A- or B-induced glucosylation of 22-kDa RhoA in HL60 cells, toxin B being more effective than toxin A. GTPgammaS-stimulated PLD activation measured with the exogenous substrate containing phosphatidylinositol 4,5-bisphosphate was also inhibited by toxin B [34].
• The 22-kDa factor induced high levels of the 26-kDa-protein mRNA and low levels of IFN-beta mRNA [35].
• The mechanism by which this mutant GH may alter the controlled secretory pathway and therefore suppress the secretion of the normal 22-kDa GH product of the normal allele is not known in detail [36].
• We have cloned the gene encoding the 24-kDa protein and show that it is expressed as a 22-kDa alpha-zein with an uncleaved signal peptide [37].

Other interactions of SRI

• Affinity chromatography using this construct identified sorcin as a Ca2+-dependent synexin-binding protein [21].
• Western blotting of the immunoprecipitates revealed that the 22-kDa protein corresponds to ALG-2 [24].
• The PEF family proteins sorcin and grancalcin interact in vivo and in vitro [25].
• Stomatin is the major protein of the microvesicular lipid rafts, whereas synexin and sorcin represent the major proteins of the nanovesicular rafts in the presence of Ca(++) [38].
• In addition, we showed that sorcin antibody immunoprecipitates ryanodine receptors from metabolically labeled cardiac myocytes along with a second protein having a molecular weight similar to that of the alpha1 subunit of cardiac L-type Ca2+ channels [28].

Analytical, diagnostic and therapeutic context of SRI

• We have also demonstrated that the level of sorcin expression in leukemia patients correlates not only directly with that of the mdr1 gene, but also inversely with patients' response to chemotherapies and overall prognosis [22].
• METHODS: Amplification of sorcin gene and mdr1 gene in K562/A02 cell detected by Northern blot, were monitored by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) in 65 AML patients and 27 normal controls, with their relationship and clinical outcame analyzed [39].
• METHODS: A semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate the transcription levels of the human sorcin gene in 95 AL patients and 27 controls [2].
• Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines [40].
• Association of sorcin with a ryanodine receptor complex was confirmed by complementary co-immunoprecipitations of sorcin with the receptor antibody [26].

References