Note | |
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Entity | Various cancers |
Prognosis | Expression levels decrease in some carcinomas. |
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| PPP1R9B expression in colon: left, normal epithelia with high levels PPPR1B; right, PPP1RB downregulation in carcinoma. |
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Oncogenesis | PPP1R9B mRNA is lost in a percentage of renal carcinomas and lung adenocarcinomas (Carnero, 2012). More interestingly, analysis of normal vs tumoral samples of tumors of the CNS showed clear downregulation of PPP1R9B in tumoral samples. Furthermore, lower levels of PPP1R9B mRNA correlates with higher grade of ovarian carcinoma and chronic myelogenous leukaemia (Carnero, 2012). PPP1R9B is also lost in 20% and reduced in another 37% of human lung tumors (Molina-Pinelo et al., 2011). PPP1R9B reduction correlates with malignant grade and p53 mutations (Carnero, 2012). The PPP1R9B gene is located in chromosome 17, at position 17q21.33, and in a cytogenetic area frequently associated with microsatellite instability and loss of heterozygosity. This region is comprised of a relatively high density of tumor suppressor genes, including known (BRCA1, NME1), putative (JUP, prohibitin), and unidentified candidates distal to the BRCA1 locus (Carnero, 2012). Most of the studies on the 17q21 locus have focused on BRCA1, which exhibits a variable frequency in LOH depending on the type of tumor, stage and marker employed, and has been extensively studied in breast carcinomas (Caduff et al., 1999; Maitra et al., 1999; Querzoli et al., 2001). However, there are few studies that suggest the existence of unknown tumor suppressor genes for breast tumors in an area that includes the locus of PPP1R9B. LOH in chromosome 17q21.3 has been observed in different tumors, including breast, ovarian, prostate, colorectal, gastric, renal and lung carcinomas, as well as in salivary gland carcinosarcoma, an extremely aggressive neoplasm (Caduff et al., 1999; Maitra et al., 1999; Querzoli et al., 2001). The markers used in some of these studies with no linkage to BRCA1 point to NME1 as a tumor suppressor gene candidate to justify the functional impact of the allelic loss. However, in different LOH studies an unidentified tumor suppressor gene nearby NME1 has been proposed. PPP1R9B is located in close proximity to NME1, at only 1 Mb, probably sharing the allelic loss in these studies. The most relevant data according to PPP1R9B LOH came from a study on primary lung carcinoma (Abujiang et al., 1998). This group performed an extensive LOH mapping in human lung cancers, using 15 highly polymorphic markers, 7 of which span 17q11-24 region. The higher LOH value appeared with the D17S588 marker, showing a 53% of loss. The D17S588 marker locates exactly within the PPP1R9B locus. These data provided the first robust data implicating PPP1R9B LOH in cancer. Closer tumor suppressor genes, such as BRCA1, were not seriously affected (6-13% LOH), nor other lung proliferative pathologies (squamous cell carcinoma and small cell carcinoma only showed minimal LOH, below 14%, for both PPP1R9B and BRCA1 markers). Several genetic linkage studies using the marker D17S588 have suggested the existence of a tumor suppressor gene distal to BRCA1 (Porter et al., 1993; Porter et al., 1994). The maximum LOD scores obtained for D17S588 were of 5,44 in an Edinburgh study of 15 families (Cohen et al., 1993) and 21,68 in an analysis of 271 breast and breast-ovarian cancer families (Easton et al., 1993, Smith et al., 1993), indicating the importance of this locus in the pathology of cancer. The D17S588 marker lies inside the PPP1R9B gene. Another study that investigated the correlation between p53 abnormalities and allelic loss of BRCA1, BRCA2 and adjacent loci in breast cancer found a strong correlation when using the D17S588 marker (Querzoli et al., 2001; Tseng et al., 1997). Again, PPP1R9B may be involved in the tumorigenic process by functioning, in association with a loss of p53 functionality, as a tumor suppressor (47,1% LOH) (Tseng et al., 1997). |
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Entity | Learning and memory, regulation of blood pressure and cardiac function |
Disease | Learning and memory defects, problems in the regulation of blood pressure and cardiac function, tumors of different origin. |
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Loss of heterozygosity (LOH) at 17q and 14q in human lung cancers. |
Abujiang P, Mori TJ, Takahashi T, Tanaka F, Kasyu I, Hitomi S, Hiai H. |
Oncogene. 1998 Dec 10;17(23):3029-33. |
PMID 9881705 |
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Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity. |
Allen PB, Zachariou V, Svenningsson P, Lepore AC, Centonze D, Costa C, Rossi S, Bender G, Chen G, Feng J, Snyder GL, Bernardi G, Nestler EJ, Yan Z, Calabresi P, Greengard P. |
Neuroscience. 2006 Jul 7;140(3):897-911. |
PMID 16600521 |
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Spinophilin stabilizes cell surface expression of alpha 2B-adrenergic receptors. |
Brady AE, Wang Q, Colbran RJ, Allen PB, Greengard P, Limbird LE. |
J Biol Chem. 2003 Aug 22;278(34):32405-12. Epub 2003 May 8. |
PMID 12738775 |
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Comparison of alterations of chromosome 17 in carcinoma of the ovary and of the breast. |
Caduff RF, Svoboda-Newman SM, Ferguson AW, Frank TS. |
Virchows Arch. 1999 Jun;434(6):517-22. |
PMID 10394886 |
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Spinophilin: a new tumor suppressor at 17q21. |
Carnero A. |
Curr Mol Med. 2012 Jun 1;12(5):528-35. |
PMID 22515982 |
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Multiple actions of spinophilin regulate mu opioid receptor function. |
Charlton JJ, Allen PB, Psifogeorgou K, Chakravarty S, Gomes I, Neve RL, Devi LA, Greengard P, Nestler EJ, Zachariou V. |
Neuron. 2008 Apr 24;58(2):238-47. |
PMID 18439408 |
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Linkage of a major breast cancer gene to chromosome 17q12-21: results from 15 Edinburgh families. |
Cohen BB, Porter DE, Wallace MR, Carothers A, Steel CM. |
Am J Hum Genet. 1993 Apr;52(4):723-9. |
PMID 8460638 |
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Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. |
Easton DF, Bishop DT, Ford D, Crockford GP. |
Am J Hum Genet. 1993 Apr;52(4):678-701. |
PMID 8460634 |
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Phosphorylation of spinophilin modulates its interaction with actin filaments. |
Hsieh-Wilson LC, Benfenati F, Snyder GL, Allen PB, Nairn AC, Greengard P. |
J Biol Chem. 2003 Jan 10;278(2):1186-94. Epub 2002 Nov 1. |
PMID 12417592 |
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Protein phosphatase 1 regulators in DNA damage signaling. |
Kuntziger T, Landsverk HB, Collas P, Syljuasen RG. |
Cell Cycle. 2011 May 1;10(9):1356-62. Epub 2011 May 1. (REVIEW) |
PMID 21451260 |
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Molecular abnormalities associated with secretory carcinomas of the breast. |
Maitra A, Tavassoli FA, Albores-Saavedra J, Behrens C, Wistuba II, Bryant D, Weinberg AG, Rogers BB, Saboorian MH, Gazdar AF. |
Hum Pathol. 1999 Dec;30(12):1435-40. |
PMID 10667421 |
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PPP1R9B (Neurabin 2): involvement and dynamics in the NK immunological synapse. |
Meng X, Kanwar N, Du Q, Goping IS, Bleackley RC, Wilkins JA. |
Eur J Immunol. 2009 Feb;39(2):552-60. |
PMID 19130477 |
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Down-regulation of spinophilin in lung tumours contributes to tumourigenesis. |
Molina-Pinelo S, Ferrer I, Blanco-Aparicio C, Peregrino S, Pastor MD, Alvarez-Vega J, Suarez R, Verge M, Marin JJ, Hernandez-Losa J, Ramon y Cajal S, Paz-Ares L, Carnero A. |
J Pathol. 2011 Sep;225(1):73-82. doi: 10.1002/path.2905. Epub 2011 May 19. |
PMID 21598252 |
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Subcellular distribution of spinophilin immunolabeling in primate prefrontal cortex: localization to and within dendritic spines. |
Muly EC, Smith Y, Allen P, Greengard P. |
J Comp Neurol. 2004 Feb 2;469(2):185-97. |
PMID 14694533 |
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Cellular and subcellular distribution of spinophilin, a PP1 regulatory protein that bundles F-actin in dendritic spines. |
Ouimet CC, Katona I, Allen P, Freund TF, Greengard P. |
J Comp Neurol. 2004 Nov 22;479(4):374-88. |
PMID 15514983 |
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Spinophilin is required for normal morphology, Ca(2+) homeostasis and contraction but dispensable for ?-adrenergic stimulation of adult cardiomyocytes. |
Petzhold D, da Costa-Goncalves AC, Gross V, Morano I. |
J Muscle Res Cell Motil. 2011 Dec;32(4-5):243-8. Epub 2011 Sep 16. |
PMID 21922228 |
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Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21. |
Porter DE, Cohen BB, Wallace MR, Smyth E, Chetty U, Dixon JM, Steel CM, Carter DC. |
Br J Surg. 1994 Oct;81(10):1512-5. |
PMID 7820489 |
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Genetic linkage analysis applied to unaffected women from families with breast cancer can discriminate high- from low-risk individuals. |
Porter DE, Steel CM, Cohen BB, Wallace MR, Carothers A, Chetty U, Carter DC. |
Br J Surg. 1993 Nov;80(11):1381-5. |
PMID 8252342 |
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Biophenotypes and survival of BRCA1 and TP53 deleted breast cancer in young women. |
Querzoli P, Albonico G, di Iasio MG, Ferretti S, Rinaldi R, Cariello A, Pedriali M, Matteuzzi M, Maestri I, Nenci I. |
Breast Cancer Res Treat. 2001 Mar;66(2):135-42. |
PMID 11437099 |
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Spinophilin: from partners to functions. |
Sarrouilhe D, di Tommaso A, Metaye T, Ladeveze V. |
Biochimie. 2006 Sep;88(9):1099-113. Epub 2006 May 17. (REVIEW) |
PMID 16737766 |
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Scaffold proteins and immune-cell signalling. |
Shaw AS, Filbert EL. |
Nat Rev Immunol. 2009 Jan;9(1):47-56. (REVIEW) |
PMID 19104498 |
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Genetic heterogeneity and localization of a familial breast-ovarian cancer gene on chromosome 17q12-q21. |
Smith SA, Easton DF, Ford D, Peto J, Anderson K, Averill D, Stratton M, Ponder M, Pye C, Ponder BA. |
Am J Hum Genet. 1993 Apr;52(4):767-76. |
PMID 8460642 |
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Impaired conditioned taste aversion learning in spinophilin knockout mice. |
Stafstrom-Davis CA, Ouimet CC, Feng J, Allen PB, Greengard P, Houpt TA. |
Learn Mem. 2001 Sep-Oct;8(5):272-8. |
PMID 11584074 |
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Allelic loss at BRCA1, BRCA2, and adjacent loci in relation to TP53 abnormality in breast cancer. |
Tseng SL, Yu IC, Yue CT, Chang SF, Chang TM, Wu CW, Shen CY. |
Genes Chromosomes Cancer. 1997 Dec;20(4):377-82. |
PMID 9408754 |
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The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein. |
Vivo M, Calogero RA, Sansone F, Calabro V, Parisi T, Borrelli L, Saviozzi S, La Mantia G. |
J Biol Chem. 2001 Apr 27;276(17):14161-9. Epub 2001 Jan 30. |
PMID 11278317 |
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Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors. |
Wang Q, Zhao J, Brady AE, Feng J, Allen PB, Lefkowitz RJ, Greengard P, Limbird LE. |
Science. 2004 Jun 25;304(5679):1940-4. |
PMID 15218143 |
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Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. |
Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P. |
Nat Neurosci. 1999 Jan;2(1):13-7. |
PMID 10195174 |
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Role of the multidomain protein spinophilin in blood pressure and cardiac function regulation. |
da Costa-Goncalves AC, Tank J, Plehm R, Diedrich A, Todiras M, Gollasch M, Heuser A, Wellner M, Bader M, Jordan J, Luft FC, Gross V. |
Hypertension. 2008 Oct;52(4):702-7. Epub 2008 Aug 18. |
PMID 18711009 |
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