Atlas of Genetics and Cytogenetics in Oncology and Haematology
PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32))
| Identity |
| Other names | DARPP-32 |
| DARPP32 | |
| FLJ20940 | |
| t-DARPP | |
| Hugo | PPP1R1B |
| Location | 17q12 |
 | |
| Genomic localization of DARPP-32, with FISH using BAC clone CTD-2019C10 (Research Genetics) that contains DARPP-32, using fluorescent in situ hybridization (FISH) on a normal metaphase spread. Arrows indicate the green FITC hybridization signals. The ideogram of chromosome 17 together with the inverted DAPI banding and FISH hybridization signals on the two chromosome 17. The FISH signals localize to chromosome band 17q12-q21. | |
| DNA/RNA |
 | |
| This schematic illustration shows the genomic structure of DARPP-32 and its transcriptional splice variant that encodes a truncated DARPP-32 protein (t-DARPP). The sequence length of the mRNA of DARPP-32 is 1,841 bp, including the untranslated 3' and 5' ends. The length of the transcriptional splice variant of DARPP-32 that encodes a truncated DARPP-32 protein (t-DARPP) is 1,502 bp. DARPP-32 and t-DARPP share an identical sequence from exon 2 to the 3' end. Each of them has seven exons. Each of DARPP-32 and t-DARPP transcripts has its own unique exon 1, where exon1 in DARPP-32 includes 548 bp whereas exon1 in t-DARPP consists of unique 207 bp that does not match with exon1 of DARPP-32. | |
| Description | DARPP-32 gene is located at 17q12. Both full length DARPP-32 and its transcriptional splice variant (t-DARPP) consist of seven exons where only exon 1 is unique in each of the two transcripts. |
| Transcription | 2 alternative transcripts |
| Pseudogene | Unknown |
| Protein |
| Description | DARPP-32 encodes a protein of 204 amino acids (about 32 kD), whereas t-DARPP encodes a 168 amino acid protein (about 28 kD). DARPP-32 contains four phosphorylation sites at Thr34, Thr75, Ser102, and Ser137, whereas t-DARPP lacks the Thr34 phosphorylation site of DARPP-32. The schematic illustration, shown above, demonstrates the phosphorylation sites of DARPP-32 and t-DARPP shown in yellow color. |
| Expression | DARPP-32 protein is highly expressed in medium-sized spiny neurons of the neostriatum. DARPP-32 was characterized as a major target for dopamine and protein kinase A signaling. Modulation of DARPP-32 phosphorylation state provides a molecular mechanism for integrating signals through several neurotransmitters and steroid hormones that stimulate dopaminoceptic neurons in various regions of the brain. Activation of PKA or PKG leads to phosphorylation of DARPP-32 at Thr34 and subsequently converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). Cdk5 can also phosphorylate DARPP-32 at Thr75 and this converts DARPP-32 into a PKA inhibitor. Expression of t-DARPP in the brain was not reported. Protein and mRNA expression of both DARPP-32 and t-DARPP are expressed at varying levels in several types of normal epithelial tissues outside the brain. DARPP-32 and t-DARPP are over-expressed in carcinomas of the breast, prostate, colon, and stomach compared with normal tissue samples. The observation that DARPP-32 and t-DARPP are frequently over-expressed in common subtypes of human cancers suggests that these proteins may play a role in tumorigenesis. The expression of t-DARPP has been shown to increase the AKT kinase activity and regulate the levels of BCL2 in cancer cells. This effect is believed to mediate resistance to drug-induced apoptosis. |
| Localisation | Cytosolic |
| Homology | Unknown |
| Mutations |
| Note | Unknown |
| Implicated in |
| Entity | Dopaminergic disorders |
| Disease | DARPP-32 plays a key role in cognitive function, and multiple brain functions. DARPP-32 is a key mediator of the biochemical, electrophysiological, transcriptional, and behavioral effects of dopamine. In this respect, DARPP-32 plays a critical role in dopaminoceptive neurons in the neostriatum (and likely in other brain regions) in signal transduction pathways regulated by a variety of neurotransmitters, neuromodulators, and neuropeptides. Abnormal signaling through DARPP-32 has been implicated in several major neurologic and psychiatric disorders. DARPP-32 may be involved in the pathogenesis of schizophrenia and plays a role in mediating the actions of a broad range of drugs of abuse. |
| Entity | Cancers |
| Oncogenesis | Over-expression of DARPP-32 and t-DARPP are associated with gastric cancer, and confer a potent anti-apoptotic function in cancer cells through a p53-independent mechanism that involves preservation of mitochondrial membrane potential and increased Bcl2 expression levels. t-DARPP transcriptionally up-regulates Bcl2 by an Akt-dependent mechanism through activation of CREB/ATF-1 transcription factors in gastric cancer. DARPP-32 is frequently over-expressed in multiple human adenocarcinomas suggesting that DARPP-32 proteins may be important in tumorigenesis. Decreased expression of DARPP-32, however, in oral premalignant and malignant lesions was observed, and thereby suggested that DARPP-32 may be a tumor suppressor in this particular malignancy. In addition, phosphorylation of DARPP-32 at Thr34 or Thr75 appears to regulate breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. |
| External links |
| Bibliography |
| DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. |
| Hemmings HC Jr, Greengard P, Tung HY, Cohen P |
| Nature. 1984 ; 310 (5977) : 503-505. |
| PMID 6087160 |
| Neuronal phosphoproteins. Mediators of signal transduction. |
| Greengard P |
| Molecular neurobiology. 1987 ; 1 (1-2) : 81-119. |
| PMID 2908293 |
| Studies of the physiological role of specific neuronal phosphoproteins. |
| Greengard P, Browning MD |
| Advances in second messenger and phosphoprotein research. 1988 ; 21 : 133-146. |
| PMID 3137955 |
| Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. |
| Halpain S, Girault JA, Greengard P |
| Nature. 1990 ; 343 (6256) : 369-372. |
| PMID 2153935 |
| Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. |
| Halpain S, Girault JA, Greengard P |
| Nature. 1990 ; 343 (6256) : 369-372. |
| PMID 2153935 |
| Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue. |
| Brenˆ© S, Lindefors N, Ehrlich M, Taubes T, Horiuchi A, Kopp J, Hall H, Sedvall G, Greengard P, Persson H |
| The Journal of neuroscience : the official journal of the Society for Neuroscience. 1994 ; 14 (3 Pt 1) : 985-998. |
| PMID 8120638 |
| Bidirectional regulation of DARPP-32 phosphorylation by dopamine. |
| Nishi A, Snyder GL, Greengard P |
| The Journal of neuroscience : the official journal of the Society for Neuroscience. 1997 ; 17 (21) : 8147-8155. |
| PMID 9334390 |
| DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. |
| Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O'Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P |
| Science (New York, N.Y.). 1998 ; 281 (5378) : 838-842. |
| PMID 9694658 |
| The DARPP-32/protein phosphatase-1 cascade: a model for signal integration. |
| Greengard P, Nairn AC, Girault JA, Ouimet CC, Snyder GL, Fisone G, Allen PB, Fienberg A, Nishi A |
| Brain research. Brain research reviews. 1998 ; 26 (2-3) : 274-284. |
| PMID 9651542 |
| Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. |
| Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC Jr, Nairn AC, Greengard P |
| Nature. 1999 ; 402 (6762) : 669-671. |
| PMID 10604473 |
| Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. |
| Greengard P, Allen PB, Nairn AC |
| Neuron. 1999 ; 23 (3) : 435-447. |
| PMID 10433257 |
| Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro. |
| Mayerhofer A, Hemmings HC Jr, Snyder GL, Greengard P, Boddien S, Berg U, Brucker C |
| The Journal of clinical endocrinology and metabolism. 1999 ; 84 (1) : 257-264. |
| PMID 9920093 |
| Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. |
| Mani SK, Fienberg AA, O'Callaghan JP, Snyder GL, Allen PB, Dash PK, Moore AN, Mitchell AJ, Bibb J, Greengard P, O'Malley BW |
| Science (New York, N.Y.). 2000 ; 287 (5455) : 1053-1056. |
| PMID 10669419 |
| Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. |
| El-Rifai W, Smith MF Jr, Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF Jr, Powell SM |
| Cancer research. 2002 ; 62 (14) : 4061-4064. |
| PMID 12124342 |
| Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. |
| Lindskog M, Svenningsson P, Pozzi L, Kim Y, Fienberg AA, Bibb JA, Fredholm BB, Nairn AC, Greengard P, Fisone G |
| Nature. 2002 ; 418 (6899) : 774-778. |
| PMID 12181566 |
| Overexpression of the 32-kilodalton dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein in common adenocarcinomas. |
| Beckler A, Moskaluk CA, Zaika A, Hampton GM, Powell SM, Frierson HF Jr, El-Rifai W |
| Cancer. 2003 ; 98 (7) : 1547-1551. |
| PMID 14508844 |
| The role of DARPP-32 in the actions of drugs of abuse. |
| Nairn AC, Svenningsson P, Nishi A, Fisone G, Girault JA, Greengard P |
| Neuropharmacology. 2004 ; 47 Suppl 1 : 14-23. |
| PMID 15464122 |
| Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. |
| Belkhiri A, Zaika A, Pidkovka N, Knuutila S, Moskaluk C, El-Rifai W |
| Cancer research. 2005 ; 65 (15) : 6583-6592. |
| PMID 16061638 |
| DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation. |
| Garcˆ‚a-Jimˆ©nez C, Zaballos MA, Santisteban P |
| Molecular endocrinology (Baltimore, Md.). 2005 ; 19 (12) : 3060-3072. |
| PMID 16020482 |
| Overexpression of DARPP-32 in colorectal adenocarcinoma. |
| Wang MS, Pan Y, Liu N, Guo C, Hong L, Fan D |
| International journal of clinical practice. 2005 ; 59 (1) : 58-61. |
| PMID 15707466 |
| Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. |
| Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH, Egan MF, Huffaker SS, Mattay VS, Kolachana B, Kleinman JE, Weinberger DR |
| The Journal of clinical investigation. 2007 ; 117 (3) : 672-682. |
| PMID 17290303 |
| t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. |
| Belkhiri A, Dar AA, Zaika A, Kelley M, El-Rifai W |
| Cancer research. 2008 ; 68 (2) : 395-403. |
| PMID 18199533 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 12-2007 | Wael El-Rifai, Abbes Belkhiri |
| Department of Surgery, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee |
| Citation |
| This paper should be referenced as such : |
| El-Rifai W, Belkhiri A . PPP1R1B (protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regulated phosphoprotein, DARPP-32)). Atlas Genet Cytogenet Oncol Haematol. December 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PPP1R1BID44096ch17q12.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Jul 2 08:26:11 2008 |
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