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Gene Review

SRI  -  sorcin

Homo sapiens

Synonyms: 22 kDa protein, CP-22, CP22, SCN, Sorcin, ...
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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


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


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


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


Analytical, diagnostic and therapeutic context of SRI


  1. Overexpression of sorcin enhances cardiac contractility in vivo and in vitro. Frank, K.F., Bölck, B., Ding, Z., Krause, D., Hattebuhr, N., Malik, A., Brixius, K., Hajjar, R.J., Schrader, J., Schwinger, R.H. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  2. Expression and clinical implications of the soluble drug resistance-related calcium-binding protein (sorcin) gene in leukemia patients. Li, G., Tan, Y., Yang, C., Zhao, C., Zhao, H., Wang, J., Xue, Y., Han, M., Qian, L., Zhao, C. Zhonghua Xue Ye Xue Za Zhi (2002) [Pubmed]
  3. Calcium-dependent translocation of sorcin to membranes: functional relevance in contractile tissue. Meyers, M.B., Zamparelli, C., Verzili, D., Dicker, A.P., Blanck, T.J., Chiancone, E. FEBS Lett. (1995) [Pubmed]
  4. Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells. Parekh, H.K., Deng, H.B., Choudhary, K., Houser, S.R., Simpkins, H. Biochem. Pharmacol. (2002) [Pubmed]
  5. Purification, cDNA cloning, and expression of human sorcin in vincristine-resistant HOB1 lymphoma cell lines. Lee, W.P. Arch. Biochem. Biophys. (1996) [Pubmed]
  6. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Fineberg, N.A., Sivakumaran, T., Roberts, A., Gale, T. International clinical psychopharmacology. (2005) [Pubmed]
  7. The pharmacodynamics of ethanol: effects on performance and judgment. Gengo, F.M., Gabos, C., Straley, C., Manning, C. Journal of clinical pharmacology. (1990) [Pubmed]
  8. A multidimensional model for characterizing tobacco dependence. Hudmon, K.S., Marks, J.L., Pomerleau, C.S., Bolt, D.M., Brigham, J., Swan, G.E. Nicotine Tob. Res. (2003) [Pubmed]
  9. A review of 19 double-blind placebo-controlled studies in social anxiety disorder (social phobia). Versiani, M. World J. Biol. Psychiatry (2000) [Pubmed]
  10. Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. Tolar, M., Marques, M.A., Harmony, J.A., Crutcher, K.A. J. Neurosci. (1997) [Pubmed]
  11. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Irobi, J., Van Impe, K., Seeman, P., Jordanova, A., Dierick, I., Verpoorten, N., Michalik, A., De Vriendt, E., Jacobs, A., Van Gerwen, V., Vennekens, K., Mazanec, R., Tournev, I., Hilton-Jones, D., Talbot, K., Kremensky, I., Van Den Bosch, L., Robberecht, W., Van Vandekerckhove, J., Broeckhoven, C., Gettemans, J., De Jonghe, P., Timmerman, V. Nat. Genet. (2004) [Pubmed]
  12. Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Hsieh, J.J., Cheng, E.H., Korsmeyer, S.J. Cell (2003) [Pubmed]
  13. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Sereda, M.W., Meyer zu Hörste, G., Suter, U., Uzma, N., Nave, K.A. Nat. Med. (2003) [Pubmed]
  14. Heparin-binding protein targeted to mitochondrial compartments protects endothelial cells from apoptosis. Olofsson, A.M., Vestberg, M., Herwald, H., Rygaard, J., David, G., Arfors, K.E., Linde, V., Flodgaard, H., Dedio, J., Müller-Esterl, W., Lundgren-Akerlund, E. J. Clin. Invest. (1999) [Pubmed]
  15. Modulation of intracellular Ca2+ levels in the heart by sorcin and FKBP12, two accessory proteins of ryanodine receptors. Valdivia, H.H. Trends Pharmacol. Sci. (1998) [Pubmed]
  16. Immunocytochemical identification and localization of the Mr 22,000 calcium-binding protein (sorcin) in an adriamycin-resistant myelogenous leukemia cell line. Sugawara, I., Mizumoto, K., Ohkochi, E., Hamada, H., Tsuruo, T., Mori, S. Jpn. J. Cancer Res. (1989) [Pubmed]
  17. Effect of impaired renal function and haemodialysis on the pharmacokinetics of aprepitant. Bergman, A.J., Marbury, T., Fosbinder, T., Swan, S., Hickey, L., Bradstreet, T.E., Busillo, J., Petty, K.J., Aiyer, K.J., Constanzer, M., Huskey, S.E., Majumdar, A. Clinical pharmacokinetics. (2005) [Pubmed]
  18. Receptor-selective retinoid agonists and teratogenic activity. Willhite, C.C., Dawson, M.I., Reichert, U. Drug Metab. Rev. (1996) [Pubmed]
  19. Preliminary assessment of captopril sonography in screening for renal artery stenosis. Gottlieb, R.H., Lieberman, J.L., Ghaed, V.N., Grossman, E.B., Waldman, D.L., Azodo, M.V., Watt, G.H., Robinette, W.B., Carson, N.L. Academic radiology. (1996) [Pubmed]
  20. Genes amplified and overexpressed in human multidrug-resistant cell lines. Van der Bliek, A.M., Baas, F., Van der Velde-Koerts, T., Biedler, J.L., Meyers, M.B., Ozols, R.F., Hamilton, T.C., Joenje, H., Borst, P. Cancer Res. (1988) [Pubmed]
  21. Calcium-dependent binding of sorcin to the N-terminal domain of synexin (annexin VII). Brownawell, A.M., Creutz, C.E. J. Biol. Chem. (1997) [Pubmed]
  22. Sorcin, an important gene associated with multidrug-resistance in human leukemia cells. Zhou, Y., Xu, Y., Tan, Y., Qi, J., Xiao, Y., Yang, C., Zhu, Z., Xiong, D. Leuk. Res. (2006) [Pubmed]
  23. Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. Pack-Chung, E., Meyers, M.B., Pettingell, W.P., Moir, R.D., Brownawell, A.M., Cheng, I., Tanzi, R.E., Kim, T.W. J. Biol. Chem. (2000) [Pubmed]
  24. Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner. Kitaura, Y., Matsumoto, S., Satoh, H., Hitomi, K., Maki, M. J. Biol. Chem. (2001) [Pubmed]
  25. The PEF family proteins sorcin and grancalcin interact in vivo and in vitro. Hansen, C., Tarabykina, S., la Cour, J.M., Lollike, K., Berchtold, M.W. FEBS Lett. (2003) [Pubmed]
  26. Association of sorcin with the cardiac ryanodine receptor. Meyers, M.B., Pickel, V.M., Sheu, S.S., Sharma, V.K., Scotto, K.W., Fishman, G.I. J. Biol. Chem. (1995) [Pubmed]
  27. Association of sorcin with drug resistance in L1210 cells. Roberts, D., Meyers, M.B., Biedler, J.L., Wiggins, L.G. Cancer Chemother. Pharmacol. (1989) [Pubmed]
  28. Sorcin associates with the pore-forming subunit of voltage-dependent L-type Ca2+ channels. Meyers, M.B., Puri, T.S., Chien, A.J., Gao, T., Hsu, P.H., Hosey, M.M., Fishman, G.I. J. Biol. Chem. (1998) [Pubmed]
  29. The scaffolding protein PSD-95 interacts with the glycine transporter GLYT1 and impairs its internalization. Cubelos, B., González-González, I.M., Giménez, C., Zafra, F. J. Neurochem. (2005) [Pubmed]
  30. Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE. Lund-Katz, S., Wehrli, S., Zaiou, M., Newhouse, Y., Weisgraber, K.H., Phillips, M.C. J. Lipid Res. (2001) [Pubmed]
  31. Salmon serum 22 kDa insulin-like growth factor-binding protein (IGFBP) is IGFBP-1. Shimizu, M., Dickey, J.T., Fukada, H., Dickhoff, W.W. J. Endocrinol. (2005) [Pubmed]
  32. Proteinase-3 induces procaspase-3 activation in the absence of apoptosis: potential role of this compartmentalized activation of membrane-associated procaspase-3 in neutrophils. Pederzoli, M., Kantari, C., Gausson, V., Moriceau, S., Witko-Sarsat, V. J. Immunol. (2005) [Pubmed]
  33. The identification and characterization of an epidermal growth factor-stimulated phosphorylation of a specific low molecular weight GTP-binding protein in a reconstituted phospholipid vesicle system. Hart, M.J., Polakis, P.G., Evans, T., Cerione, R.A. J. Biol. Chem. (1990) [Pubmed]
  34. Effects of Clostridium difficile toxin A and toxin B on phospholipase D activation in human promyelocytic leukemic HL60 cells. Ohguchi, K., Banno, Y., Nakashima, S., Kato, N., Watanabe, K., Lyerly, D.M., Nozawa, Y. Infect. Immun. (1996) [Pubmed]
  35. Induction of a 26-kDa-protein mRNA in human cells treated with an interleukin-1-related, leukocyte-derived factor. Content, J., De Wit, L., Poupart, P., Opdenakker, G., Van Damme, J., Billiau, A. Eur. J. Biochem. (1985) [Pubmed]
  36. Impact of del32-71-GH (exon 3 skipped GH) on intracellular GH distribution, secretion and cell viability: a quantitative confocal microscopy analysis. Salemi, S., Yousefi, S., Eblé, A., Deladoëy, J., Mullis, P.E. Horm. Res. (2006) [Pubmed]
  37. A defective signal peptide in the maize high-lysine mutant floury 2. Coleman, C.E., Lopes, M.A., Gillikin, J.W., Boston, R.S., Larkins, B.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  38. Ca(++)-dependent vesicle release from erythrocytes involves stomatin-specific lipid rafts, synexin (annexin VII), and sorcin. Salzer, U., Hinterdorfer, P., Hunger, U., Borken, C., Prohaska, R. Blood (2002) [Pubmed]
  39. Expression and clinical implication of soluble resistance-associated calcium-binding protein gene and multi-drug resistance gene in leukemia. Li, G., Tan, Y., Yang, C., Zhao, C., Zhao, H., Wang, J., Xue, Y., Han, M., Qian, L., Zhao, C. Zhonghua Zhong Liu Za Zhi (2002) [Pubmed]
  40. Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling. Takeda, T., Asahi, M., Yamaguchi, O., Hikoso, S., Nakayama, H., Kusakari, Y., Kawai, M., Hongo, K., Higuchi, Y., Kashiwase, K., Watanabe, T., Taniike, M., Nakai, A., Nishida, K., Kurihara, S., Donoviel, D.B., Bernstein, A., Tomita, T., Iwatsubo, T., Hori, M., Otsu, K. FASEB J. (2005) [Pubmed]
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