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PLCD1 (phospholipase C, delta 1)

Identity

HGNC (Hugo) PLCD1
LocusID (NCBI) 5333
Location 3p22.2
Location_base_pair Starts at 38048987 and ends at 38066278 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order The PLCD1 gene is located between the VILL gene and the DLEC1 gene.
 
  PLCD1 starts at 38048987 bp and ends at 38071253 bp from pter on Chr3p22-p21.3 and located between VILL and DLEC1 gene.

DNA/RNA

 
  Closed and opened boxes represent coding and non-coding sequences of PLCD1 gene, respectively.
Description The PLCD1 gene is a functioning gene and contains 15 exons and spans 22.17 kb.
Transcription The variant 1 (NM_001130964) encodes the longer isoform 1 (NP_001124436). The variant 2 (NM_006225.3) contains an alternate 5' terminal exon compared to transcript variant 1, and initiates translation from an in-frame upstream AUG, resulting in a shorter isoform 2 (NP_006216) with a different N-terminus compared to isoform 1.

Protein

 
  Protein domain organization of the mammalian PLCD1.
Description The deduced 777-amino acid isoform 1 (NM_001130964) and 756-amino acid isoform 2 (NP_006216) shares 95% sequence homology with the rat protein. They contain a N-terminal PH domain, 2 EF-hand1 domains, PI-PLC X-box, PI-PLC Y-box and C2 region.
Expression Expressed high or medium in CNS (brain), hematopoietic (blood), liver and pancreas, digestive (GI-tract), respiratory (lung), male and female tissues, placenta, urinary tract (kidney) skin and soft tissues but no expression in cardio vascular and endocrine tissues.
Localisation Intracellular: cytoplasm and nucleus.
Function Catalyzing the hydrolysis of phosphatidylinositol 4,5 biphosphate to generate diacylglycerol and inositol 1,4,5 triphosphate. Mediating a wide variety of cellular stimuli. Shuttling between the nucleus and the cytoplasm, and nuclear import is mediated by its Ca2+-dependent interaction with importin beta 1. Playing an important suppressive role in the development and progression of cancers such as esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC).
Homology The PLCD1 gene is conserved in dog, cow, mouse, rat, chicken, zebrafish, and A. thaliana.

Mutations

 
  The mutation location is highlighted in red and this mutation occured in 17% (1/6) skin samples.
AA Mutation: p.E226K (Substitution - Missense).
CDS Mutation: c.676G>A (Substitution).

Implicated in

Entity Esophageal squamous cell carcinoma
Prognosis Firstly, four commonly deleted regions (CDRs) at 3p26.3, 3p22, 3p21.3 and 3p14.2 were identified. Absent and down-regulated expression of several candidate TSGs, including CHL1, PCAF, RBMS3, PLCD1 and CACNA2D3, were detected in primary ESCC tumors and ESCC cell lines. These results provided evidence that minimal deleted regions at 3p26.3, 3p22, 3p21.3 and 3p14.2 containing potential TSGs may contribute to the pathogenesis of esophageal cancer.
Secondly, absent expression of PLC delta 1 was detected in 26 of 50 (52%) primary ESCCs and 4 of 9 (44.4%) ESCC cell lines, which was significantly associated with DNA copy number loss and promoter hypermethylation (P < 0.05). Functional studies showed that PLC delta 1 was able to suppress both in vitro and in vivo tumorigenic ability of ESCC cells, including foci formation, colony formation in soft agar, and tumor formation in nude mice. The tumor-suppressive mechanism of PLC delta 1 was associated with its role in the cell cycle arrest at the G(1)-S checkpoint by up-regulation of p21 and down-regulation of phosphorylated Akt (Ser(473)). In addition, down-regulation of PLC delta 1 protein was significantly correlated with ESCC metastasis (P = 0.014), which was associated with its function in increasing cell adhesion and inhibiting cell mobility. These results suggest that PLC delta 1 plays an important suppressive role in the development and progression of ESCC.
  
Entity Breast carcinoma
Prognosis PLCD1 are more highly expressed in the transformed cell lines compared to MCF-10A. To test whether PLCd1 or PLCd3 played any role in tumor cell proliferation or cell migration. RNAi mediated knockdown of PLCD1 reduced proliferation of the MDA-MB-231 cells. Morphological changes including cell rounding, and surface blebbing and nuclear fragmentation were observed. These changes were accompanied by reductions in cell migration activities. On the other hand, PLCD1 knockdown failed to cause comparable morphological changes in the normal MCF-10A line, but did reduce cell proliferation and migration. Taken together, these data are consistent with the idea that PLCD1 support the growth and migration of normal and neoplastic mammary epithelial cells in vitro.
However there is contrasted results published in another paper. Their results suggested that PLCD1 is a functional tumor suppressor inducing G(2)/M arrest and frequently methylated in breast cancer.
  
Entity Gastric cancer
Prognosis Located at the important tumor suppressor locus, 3p22, PLCD1 encodes an enzyme that mediates regulatory signaling of energy metabolism, calcium homeostasis and intracellular movements. We identified PLCD1 as a downregulated gene in aerodigestive carcinomas through expression profiling and epigenetic characterization. We found that PLCD1 was expressed in all normal adult tissues but low or silenced in 84% (16/19) gastric cancer cell lines, well correlated with its CpG island (CGI) methylation status. Methylation was further detected in 62% (61/98) gastric primary tumors, but none of normal gastric mucosa tissues. PLCD1 methylation was significantly correlated with tumor high stage. Detailed methylation analysis of 37 CpG sites at the PLCD1 CGI by bisulfite genomic sequencing confirmed its methylation. PLCD1 silencing could be reversed by pharmacological demethylation with 5-aza-2'-deoxycytidine, indicating a direct epigenetic silencing. Ectopic expression of PLCD1 in silenced gastric tumor cells dramatically inhibited their clonogenicity and migration, possibly through downregulating MMP7 expression and hampering the reorganization of cytoskeleton through cofilin inactivation by phosphorylation. Thus, epigenetic inactivation of PLCD1 is common and tumor-specific in gastric cancer, and PLCD1 acts as a functional tumor suppressor involved in gastric carcinogenesis.
  
Entity Colon carcinomas
Prognosis Decreased levels of the PLC delta 1 protein were seen in most colon carcinomas (12 of 13 paired samples) and PLC delta 1 protein was not detected in any of the carcinoma cell lines.
  
Entity Rat colon neoplasms
Prognosis The expression of PLC-delta expression in rat colon neoplasms induced by methylazoxymethanol (MAM) acetate was examined. Large-bowel neoplasms were observed in five of 10 rats given MAM acetate 40 weeks after treatment. PLC-delta expression in the neoplasms was not detected by northern blot analysis, and a low level of expression was detected by immunoblot analysis, although PLC-delta expression was apparent in the non-neoplastic colon mucosae of MAM acetate-treated rats as well as in the colon mucosae of control rats.
  
Entity Insulinoma
Note Insulinoma MIN6 cells.
Prognosis To study the effects of enhanced phosphoinositide hydrolysis on insulin secretion, phosphoinositide-specific phospholipase Cbeta1 (PLCbeta1) or PLCdelta1 was overexpressed in insulinoma MIN6 cells via adenoviral vectors. Inositol phosphate production stimulated by KCl or glucose in both PLCbeta1- and PLCdelta1-overexpressing cells were greater than that in control cells, reduced phosphatidylinositol-4,5-bisphosphate levels were observed in these cells stimulated by NaF or KCl. These data suggest that excessive phosphoinositide hydrolysis inhibits secretagogue-induced insulin release in MIN6 cells.
  
Entity Pheochromocytoma
Note Pheochromocytoma PC12 cells.
Prognosis PLCD1 is recruited from the cytoplasm to lipid rafts after CCH-induced Ca2+ mobilization following the activation of PLCbeta by GPCR and PLCD1 is activated only in lipid rafts by localized capacitative entry of extracellular Ca2+. PLCD1, p122RhoGAP and RhoA in combination could constitute a unique functional unit for the regulation of both phosphoinositide/Ca2+ signaling and the actin cytoskeleton in the periphery of specified membrane domains. This would provide further insights into the molecular mechanisms of cancer development.
  

External links

Nomenclature
HGNC (Hugo)PLCD1   9060
Cards
AtlasPLCD1ID43927ch3p22
Entrez_Gene (NCBI)PLCD1  5333  phospholipase C, delta 1
GeneCards (Weizmann)PLCD1
Ensembl (Hinxton)ENSG00000187091 [Gene_View]  chr3:38048987-38066278 [Contig_View]  PLCD1 [Vega]
ICGC DataPortalENSG00000187091
AceView (NCBI)PLCD1
Genatlas (Paris)PLCD1
WikiGenes5333
SOURCE (Princeton)NM_001130964 NM_006225
Genomic and cartography
GoldenPath (UCSC)PLCD1  -  3p22.2   chr3:38048987-38066278 -  3p22-p21.3   [Description]    (hg19-Feb_2009)
EnsemblPLCD1 - 3p22-p21.3 [CytoView]
Mapping of homologs : NCBIPLCD1 [Mapview]
OMIM151600   602142   
Gene and transcription
Genbank (Entrez)AB209862 AK090774 AK098690 AK127813 AK292324
RefSeq transcript (Entrez)NM_001130964 NM_006225
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_031922 NT_022517 NW_001838877 NW_004929309
Consensus coding sequences : CCDS (NCBI)PLCD1
Cluster EST : UnigeneHs.80776 [ NCBI ]
CGAP (NCI)Hs.80776
Alternative Splicing : Fast-db (Paris)GSHG0021613
Alternative Splicing GalleryENSG00000187091
Gene ExpressionPLCD1 [ NCBI-GEO ]     PLCD1 [ SEEK ]   PLCD1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP51178 (Uniprot)
NextProtP51178  [Medical]
With graphics : InterProP51178
Splice isoforms : SwissVarP51178 (Swissvar)
Catalytic activity : Enzyme3.1.4.11 [ Enzyme-Expasy ]   3.1.4.113.1.4.11 [ IntEnz-EBI ]   3.1.4.11 [ BRENDA ]   3.1.4.11 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)C2 (PS50004)    EF_HAND_1 (PS00018)    EF_HAND_2 (PS50222)    PH_DOMAIN (PS50003)    PIPLC_X_DOMAIN (PS50007)    PIPLC_Y_DOMAIN (PS50008)   
Domains : Interpro (EBI)C2_dom    EF-hand-dom_pair    EF_Hand_1_Ca_BS    EF_hand_dom    PH_like_dom    PI-PLC_fam    PLC-delta1    PLC-like_Pdiesterase_TIM-brl    Pleckstrin_homology    PLipase_C_EF-hand-like    PLipase_C_PInositol-sp_X_dom    PLipase_C_Pinositol-sp_Y   
Related proteins : CluSTrP51178
Domain families : Pfam (Sanger)C2 (PF00168)    EF-hand_like (PF09279)    PI-PLC-X (PF00388)    PI-PLC-Y (PF00387)   
Domain families : Pfam (NCBI)pfam00168    pfam09279    pfam00388    pfam00387   
Domain families : Smart (EMBL)C2 (SM00239)  EFh (SM00054)  PH (SM00233)  PLCXc (SM00148)  PLCYc (SM00149)  
DMDM Disease mutations5333
Blocks (Seattle)P51178
Human Protein AtlasENSG00000187091
Peptide AtlasP51178
HPRD09073
IPIIPI00746030   IPI00016461   
Protein Interaction databases
DIP (DOE-UCLA)P51178
IntAct (EBI)P51178
FunCoupENSG00000187091
BioGRIDPLCD1
IntegromeDBPLCD1
STRING (EMBL)PLCD1
Ontologies - Pathways
QuickGOP51178
Ontology : AmiGOangiogenesis  phosphatidylinositol phospholipase C activity  signal transducer activity  calcium ion binding  cytoplasm  cytosol  plasma membrane  phospholipid metabolic process  lipid catabolic process  GTPase activating protein binding  intracellular signal transduction  regulation of cell proliferation  inositol phosphate metabolic process  small molecule metabolic process  labyrinthine layer blood vessel development  extracellular vesicular exosome  
Ontology : EGO-EBIangiogenesis  phosphatidylinositol phospholipase C activity  signal transducer activity  calcium ion binding  cytoplasm  cytosol  plasma membrane  phospholipid metabolic process  lipid catabolic process  GTPase activating protein binding  intracellular signal transduction  regulation of cell proliferation  inositol phosphate metabolic process  small molecule metabolic process  labyrinthine layer blood vessel development  extracellular vesicular exosome  
Pathways : BIOCARTAPhospholipase C d1 in phospholipid associated cell signaling [Genes]   
Pathways : KEGGInositol phosphate metabolism    Calcium signaling pathway    Phosphatidylinositol signaling system    Thyroid hormone signaling pathway   
REACTOMEP51178 [protein]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
Protein Interaction DatabasePLCD1
Wikipedia pathwaysPLCD1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PLCD1
SNP (GeneSNP Utah)PLCD1
SNP : HGBasePLCD1
Genetic variants : HAPMAPPLCD1
1000_GenomesPLCD1 
ICGC programENSG00000187091 
CONAN: Copy Number AnalysisPLCD1 
Somatic Mutations in Cancer : COSMICPLCD1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)3:38048987-38066278
Mutations and Diseases : HGMDPLCD1
OMIM151600    602142   
MedgenPLCD1
GENETestsPLCD1
Disease Genetic AssociationPLCD1
Huge Navigator PLCD1 [HugePedia]  PLCD1 [HugeCancerGEM]
Genomic VariantsPLCD1  PLCD1 [DGVbeta]
Exome VariantPLCD1
dbVarPLCD1
ClinVarPLCD1
snp3D : Map Gene to Disease5333
General knowledge
Homologs : HomoloGenePLCD1
Homology/Alignments : Family Browser (UCSC)PLCD1
Phylogenetic Trees/Animal Genes : TreeFamPLCD1
Chemical/Protein Interactions : CTD5333
Chemical/Pharm GKB GenePA33388
Clinical trialPLCD1
Cancer Resource (Charite)ENSG00000187091
Other databases
Probes
Litterature
PubMed64 Pubmed reference(s) in Entrez
CoreMinePLCD1
GoPubMedPLCD1
iHOPPLCD1

Bibliography

Reduced expression of phospholipase C-delta, a signal-transducing enzyme, in rat colon neoplasms induced by methylazoxymethanol acetate.
Yoshimi N, Wang A, Makita H, Suzui M, Mori H, Okano Y, Banno Y, Nozawa Y.
Mol Carcinog. 1994 Dec;11(4):192-6.
PMID 7528022
 
Expression of phospholipases gamma 1, beta 1, and delta 1 in primary human colon carcinomas and colon carcinoma cell lines.
Nomoto K, Tomita N, Miyake M, Xhu DB, LoGerfo PR, Weinstein IB.
Mol Carcinog. 1995 Mar;12(3):146-52.
PMID 7893368
 
Genomic structure of the human PLCD1 (phospholipase C delta 1) locus on 3p22-->p21.3.
Ishikawa S, Takahashi T, Ogawa M, Nakamura Y.
Cytogenet Cell Genet. 1997;78(1):58-60.
PMID 9345909
 
Enhanced phosphoinositide hydrolysis via overexpression of phospholipase C beta1 or delta1 inhibits stimulus-induced insulin release in insulinoma MIN6 cells.
Ishihara H, Wada T, Kizuki N, Asano T, Yazaki Y, Kikuchi M, Oka Y.
Biochem Biophys Res Commun. 1999 Jan 8;254(1):77-82.
PMID 9920735
 
Characterization of a novel tumor-suppressor gene PLC delta 1 at 3p22 in esophageal squamous cell carcinoma.
Fu L, Qin YR, Xie D, Hu L, Kwong DL, Srivastava G, Tsao SW, Guan XY.
Cancer Res. 2007 Nov 15;67(22):10720-6.
PMID 18006814
 
Single-nucleotide polymorphism-mass array reveals commonly deleted regions at 3p22 and 3p14.2 associate with poor clinical outcome in esophageal squamous cell carcinoma.
Qin YR, Fu L, Sham PC, Kwong DL, Zhu CL, Chu KK, Li Y, Guan XY.
Int J Cancer. 2008 Aug 15;123(4):826-30.
PMID 18508313
 
Recruitment and activation of phospholipase C (PLC)-delta1 in lipid rafts by muscarinic stimulation of PC12 cells: contribution of p122RhoGAP/DLC1, a tumor-suppressing PLCdelta1 binding protein.
Yamaga M, Kawai K, Kiyota M, Homma Y, Yagisawa H.
Adv Enzyme Regul. 2008;48:41-54. Epub 2007 Nov 19.
PMID 18157946
 
Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer.
Hu XT, Zhang FB, Fan YC, Shu XS, Wong AH, Zhou W, Shi QL, Tang HM, Fu L, Guan XY, Rha SY, Tao Q, He C.
Oncogene. 2009 Jul 2;28(26):2466-75. Epub 2009 May 18.
PMID 19448674
 
Expression and function of phospholipase C in breast carcinoma.
Rebecchi MJ, Raghubir A, Scarlata S, Hartenstine MJ, Brown T, Stallings JD.
Adv Enzyme Regul. 2009;49(1):59-73. Epub 2009 Jan 20.
PMID 19344632
 
PLCD1 is a functional tumor suppressor inducing G(2)/M arrest and frequently methylated in breast cancer.
Xiang T, Li L, Fan Y, Jiang Y, Ying Y, Putti TC, Tao Q, Ren G.
Cancer Biol Ther. 2010 Sep;10(5):520-7. Epub 2010 Sep 21.
PMID 20657189
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written01-2011Xiaotong Hu
Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China

Citation

This paper should be referenced as such :
Hu, X
PLCD1 (phospholipase C, delta 1)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(8):670-673.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PLCD1ID43927ch3p22.html

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indexed on : Sat Nov 8 16:51:10 CET 2014

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