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PHLDA1 (pleckstrin homology-like domain, family A, member 1)

Written2014-01Maria Aparecida Nagai
Discipline of Oncology, Department of Radiology, Oncology, Medical School, University of Sao Paulo, Center for Translational Investigation in Oncology, Cancer Institute from Sao Paulo State, Sao Paulo, Brazil

(Note : for Links provided by Atlas : click)

Identity

Alias_namespleckstrin homology-like domain
Alias_symbol (synonym)TDAG51
DT1P1B11
PHRIP
Other alias
HGNC (Hugo) PHLDA1
LocusID (NCBI) 22822
Atlas_Id 41707
Location 12q21.2  [Link to chromosome band 12q21]
Location_base_pair Starts at 76025447 and ends at 76031776 bp from pter ( according to hg19-Feb_2009)  [Mapping PHLDA1.png]
Local_order Minus strand.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PHLDA1 (12q21.2) / GSN (9q33.2)PHLDA1 (12q21.2) / MBTD1 (17q21.33)PHLDA1 (12q21.2) / PHLDA1 (12q21.2)
PRRC2C (1q24.3) / PHLDA1 (12q21.2)

DNA/RNA

Description PHLDA1 gene contains 2 exons, 1 intervening sequence and spans 6,3 kb of genomic DNA.
Transcription 1,2 kb mRNA.
Pseudogene Not identified.

Protein

 
  Schematic representation of the modular structure of PHLDA1 protein. PHL: pleckstrin homology-like domain spanning amino acids residues from 150 to 283; QQ: proline/glutamine rich sequence (aa residues from 189 to 204); PQ: proline-glutamine tracts (aa residues from 311 to 346); PH: proline-histidine-rich tracts (aa residues from 352 to 389); *: indicates phosphorylation sites.
Description The PHLDA1 gene encodes for a 401 amino acid protein that is a member of the evolutionarily conserved pleckstrin homology-like domain family. PHLDA1 protein has a modular structure containing a central pleckstrin homology-like domain (PHL) and prolin-glutamine (PQ) and proline-histidine (PH) repeats in the C-terminal region (see figure above).
Expression PHLDA1 is widely expressed in mammalian tissues displaying cytoplasmic, vesicle membrane, plasma membrane and nuclear subcellular localization. PHLDA1 expression is up-regulated by estrogen, IGF-1 (insulin-like growth factor 1), FGF (fibroblast growth factor), TPA (phorbol ester), and ER (endoplamic reticulum)-stress agents such as homocysteine, tunicamicyne, and farnesol.
Localisation Cytoplasm, vesicle membrane, plasma membrane, nucleus.
Function Protein binding. Several evidences have implicate PHLDA1 as a potential transcriptional activator that acts as a pro-apoptotic and antiproliferative factor, however the mechanisms by which PHLDA1 mediates cell survival is still under investigation.
Homology PHLDA2 (pleckstrin homology-like domain, family A, member 2) and PHLDA3 (pleckstrin homology-like domain, family A, member 3) are paralogs for PHLDA1.

Mutations

Note Short genetic variation - dbSNP: rs139162669, rs73385441, rs74620794, rs147230079, rs76437300, rs186978611, rs140610935, rs144470255, rs79545253, rs147644129.

Implicated in

Note
  
Entity Melanoma
Note PHLDA1 expression was associated with reduced cell growth and colony formation and with increased apoptotic rates and drug sensitivity in melanoma cell lines. Loss of PHLDA1 has been correlated with melanoma progression (Neef et al., 2002).
  
  
Entity Breast cancer
Note Down-regulation of PHLDA1 mRNA and protein expression is frequently observed in primary invasive breast tumours. Down-regulation of PHLDA1 protein has been shown to be a strong predictor of poor prognosis for breast cancer patients, indicating that reduced PHLDA1 expression contribute for breast cancer progression and might serve as useful prognostic biomarker of disease outcome (Nagai et al., 2007).
  
  
Entity Oral cancer
Note Reduced expression of PHLDA1 was observed in 60,7% of oral squamous cell carcinomas (OSCC), especially in well-differentiated tumors. Positive PHLDA1 immunostaining was associated with advanced clinical stages of the disease, suggesting that PHLDA1 has a functional role in oral tumorigenesis. Overall and disease-free survival rates were significantly better in patients with tumors that were negative for PHLDA1, and a multivariate analysis suggested that PHLDA1 is an independent prognostic factor in OSCC patients (Coutinho-Camillo et al., 2013).
  
  
Entity Colon cancer
Note Altered PHLDA1 expression has been shown to be associated with the process of intestinal tumorigenesis (Sakthianandeswaren et al., 2011).
  
  
Entity Basal cell carcinoma
Note PHLDA1 has also been shown to be a follicular and epithelial stem cell marker (Ohyama et al., 2006; Sakthianandeswaren et al., 2011) with potential to differentiates between trichoepithelioma and basal cell carcinoma (Sellheyer and Nelson, 2011).
  
  
Entity Atherosclerosis
Note In vivo and in vitro studies demonstrated that increased PHLDA1 expression induced by homocysteine promotes detachment-mediated programmed cell death and contributes to the development of atherosclerosis (Hossain et al., 2003). Genetic variant in an intergenic region of the PHLDA1 gene (rs2367446) has been shown to be associated with the development of cardiovascular diseases (Hossain et al., 2013).
  
  
Entity Epilepsy
Note PHLDA1 expression has been shown to be higher in the anterior temporal neocortex from patients with intractable epilepsy when compared with the levels observed in the neocortex from the control group, suggesting a possible association of PHLDA1 in the physiopathology of the disease (Xi et al., 2007).
  

Bibliography

Expression of PAR-4 and PHLDA1 is prognostic for overall and disease-free survival in oral squamous cell carcinomas.
Coutinho-Camillo CM, Lourenco SV, Nonogaki S, Vartanian JG, Nagai MA, Kowalski LP, Soares FA.
Virchows Arch. 2013 Jul;463(1):31-9. doi: 10.1007/s00428-013-1438-9. Epub 2013 Jun 9.
PMID 23748915
 
A novel pleckstrin homology-related gene family defined by Ipl/Tssc3, TDAG51, and Tih1: tissue-specific expression, chromosomal location, and parental imprinting.
Frank D, Mendelsohn CL, Ciccone E, Svensson K, Ohlsson R, Tycko B.
Mamm Genome. 1999 Dec;10(12):1150-9.
PMID 10594239
 
Deficiency of TDAG51 protects against atherosclerosis by modulating apoptosis, cholesterol efflux, and peroxiredoxin-1 expression.
Hossain GS, Lynn EG, Maclean KN, Zhou J, Dickhout JG, Lhotak S, Trigatti B, Capone J, Rho J, Tang D, McCulloch CA, Al-Bondokji I, Malloy MJ, Pullinger CR, Kane JP, Li Y, Shiffman D, Austin RC.
J Am Heart Assoc. 2013 May 17;2(3):e000134. doi: 10.1161/JAHA.113.000134.
PMID 23686369
 
PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer.
Johnson EO, Chang KH, de Pablo Y, Ghosh S, Mehta R, Badve S, Shah K.
J Cell Sci. 2011 Aug 15;124(Pt 16):2711-22. doi: 10.1242/jcs.084970.
PMID 21807936
 
Assignment of the human PHLDA1 gene to chromosome 12q15 by radiation hybrid mapping.
Kuske MD, Johnson JP.
Cytogenet Cell Genet. 2000;89(1-2):1.
PMID 10894922
 
Transcriptional up-regulation of PHLDA1 by 17beta-estradiol in MCF-7 breast cancer cells.
Marchiori AC, Casolari DA, Nagai MA.
Braz J Med Biol Res. 2008 Jul;41(7):579-82. Epub 2008 Jun 30.
PMID 18641796
 
Down-regulation of PHLDA1 gene expression is associated with breast cancer progression.
Nagai MA, Fregnani JH, Netto MM, Brentani MM, Soares FA.
Breast Cancer Res Treat. 2007 Nov;106(1):49-56. Epub 2007 Jan 9.
PMID 17211533
 
PHLDA1 (pleckstrin homology-like domain, family A, member).
Nagai MA.
Encyclopedia of Signaling Molecules 2012, pp 1365 - 1369. ISBN: 978-4419-04060-7 (Editor: Sandun Choi)
 
Identification of the human PHLDA1/TDAG51 gene: down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation.
Neef R, Kuske MA, Prols E, Johnson JP.
Cancer Res. 2002 Oct 15;62(20):5920-9.
PMID 12384558
 
Regulation of T-cell death-associated gene 51 (TDAG51) expression in human T-cells.
Oberg HH, Sipos B, Kalthoff H, Janssen O, Kabelitz D.
Cell Death Differ. 2004 Jun;11(6):674-84.
PMID 15002043
 
Characterization and isolation of stem cell-enriched human hair follicle bulge cells.
Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, Brady JN, Udey MC, Vogel JC.
J Clin Invest. 2006 Jan;116(1):249-60.
PMID 16395407
 
A novel gene product that couples TCR signaling to Fas(CD95) expression in activation-induced cell death.
Park CG, Lee SY, Kandala G, Lee SY, Choi Y.
Immunity. 1996 Jun;4(6):583-91.
PMID 8673705
 
PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis.
Sakthianandeswaren A, Christie M, D'Andreti C, Tsui C, Jorissen RN, Li S, Fleming NI, Gibbs P, Lipton L, Malaterre J, Ramsay RG, Phesse TJ, Ernst M, Jeffery RE, Poulsom R, Leedham SJ, Segditsas S, Tomlinson IP, Bernhard OK, Simpson RJ, Walker F, Faux MC, Church N, Catimel B, Flanagan DJ, Vincan E, Sieber OM.
Cancer Res. 2011 May 15;71(10):3709-19. doi: 10.1158/0008-5472.CAN-10-2342. Epub 2011 May 10.
PMID 21558389
 
Follicular stem cell marker PHLDA1 (TDAG51) is superior to cytokeratin-20 in differentiating between trichoepithelioma and basal cell carcinoma in small biopsy specimens.
Sellheyer K, Nelson P.
J Cutan Pathol. 2011 Jul;38(7):542-50. doi: 10.1111/j.1600-0560.2011.01693.x. Epub 2011 Feb 24.
PMID 21352265
 
TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival.
Toyoshima Y, Karas M, Yakar S, Dupont J, Lee Helman, LeRoith D.
J Biol Chem. 2004 Jun 11;279(24):25898-904. Epub 2004 Mar 22.
PMID 15037619
 
TDAG51 in the anterior temporal neocortex of patients with intractable epilepsy.
Xi ZQ, Wang LY, Sun JJ, Liu XZ, Zhu X, Xiao F, Guan LF, Li JM, Wang L, Wang XF.
Neurosci Lett. 2007 Sep 20;425(1):53-8. Epub 2007 Aug 15.
PMID 17870236
 

Citation

This paper should be referenced as such :
MA Nagai
PHLDA1 (pleckstrin homology-like domain, family A, member 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(9):652-654.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PHLDA1ID41707ch12q15.html


External links

Nomenclature
HGNC (Hugo)PHLDA1   8933
Cards
AtlasPHLDA1ID41707ch12q15
Entrez_Gene (NCBI)PHLDA1  22822  pleckstrin homology like domain family A member 1
AliasesDT1P1B11; PHRIP; TDAG51
GeneCards (Weizmann)PHLDA1
Ensembl hg19 (Hinxton)ENSG00000139289 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000139289 [Gene_View]  chr12:76025447-76031776 [Contig_View]  PHLDA1 [Vega]
ICGC DataPortalENSG00000139289
TCGA cBioPortalPHLDA1
AceView (NCBI)PHLDA1
Genatlas (Paris)PHLDA1
WikiGenes22822
SOURCE (Princeton)PHLDA1
Genetics Home Reference (NIH)PHLDA1
Genomic and cartography
GoldenPath hg38 (UCSC)PHLDA1  -     chr12:76025447-76031776 -  12q15   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PHLDA1  -     12q15   [Description]    (hg19-Feb_2009)
EnsemblPHLDA1 - 12q15 [CytoView hg19]  PHLDA1 - 12q15 [CytoView hg38]
Mapping of homologs : NCBIPHLDA1 [Mapview hg19]  PHLDA1 [Mapview hg38]
OMIM605335   
Gene and transcription
Genbank (Entrez)AF220656 AK026181 AK304224 BC017756 BC018929
RefSeq transcript (Entrez)NM_007350
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PHLDA1
Cluster EST : UnigeneHs.602085 [ NCBI ]
CGAP (NCI)Hs.602085
Alternative Splicing GalleryENSG00000139289
Gene ExpressionPHLDA1 [ NCBI-GEO ]   PHLDA1 [ EBI - ARRAY_EXPRESS ]   PHLDA1 [ SEEK ]   PHLDA1 [ MEM ]
Gene Expression Viewer (FireBrowse)PHLDA1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)22822
GTEX Portal (Tissue expression)PHLDA1
Human Protein AtlasENSG00000139289-PHLDA1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8WV24   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8WV24  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8WV24
Splice isoforms : SwissVarQ8WV24
PhosPhoSitePlusQ8WV24
Domains : Interpro (EBI)PH_dom-like    PH_domain   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Domain families : Smart (EMBL)PH (SM00233)  
Conserved Domain (NCBI)PHLDA1
DMDM Disease mutations22822
Blocks (Seattle)PHLDA1
SuperfamilyQ8WV24
Human Protein Atlas [tissue]ENSG00000139289-PHLDA1 [tissue]
Peptide AtlasQ8WV24
HPRD05625
IPIIPI00025463   IPI00909889   
Protein Interaction databases
DIP (DOE-UCLA)Q8WV24
IntAct (EBI)Q8WV24
FunCoupENSG00000139289
BioGRIDPHLDA1
STRING (EMBL)PHLDA1
ZODIACPHLDA1
Ontologies - Pathways
QuickGOQ8WV24
Ontology : AmiGOG2/M transition of mitotic cell cycle  protein binding  nucleus  nucleolus  cytosol  apoptotic process  cytoplasmic vesicle  FasL biosynthetic process  
Ontology : EGO-EBIG2/M transition of mitotic cell cycle  protein binding  nucleus  nucleolus  cytosol  apoptotic process  cytoplasmic vesicle  FasL biosynthetic process  
REACTOMEQ8WV24 [protein]
REACTOME PathwaysR-HSA-8854521 [pathway]   
NDEx NetworkPHLDA1
Atlas of Cancer Signalling NetworkPHLDA1
Wikipedia pathwaysPHLDA1
Orthology - Evolution
OrthoDB22822
GeneTree (enSembl)ENSG00000139289
Phylogenetic Trees/Animal Genes : TreeFamPHLDA1
HOVERGENQ8WV24
HOGENOMQ8WV24
Homologs : HomoloGenePHLDA1
Homology/Alignments : Family Browser (UCSC)PHLDA1
Gene fusions - Rearrangements
Tumor Fusion PortalPHLDA1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPHLDA1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PHLDA1
dbVarPHLDA1
ClinVarPHLDA1
1000_GenomesPHLDA1 
Exome Variant ServerPHLDA1
ExAC (Exome Aggregation Consortium)ENSG00000139289
GNOMAD BrowserENSG00000139289
Genetic variants : HAPMAP22822
Genomic Variants (DGV)PHLDA1 [DGVbeta]
DECIPHERPHLDA1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPHLDA1 
Mutations
ICGC Data PortalPHLDA1 
TCGA Data PortalPHLDA1 
Broad Tumor PortalPHLDA1
OASIS PortalPHLDA1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPHLDA1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPHLDA1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PHLDA1
DgiDB (Drug Gene Interaction Database)PHLDA1
DoCM (Curated mutations)PHLDA1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PHLDA1 (select a term)
intoGenPHLDA1
NCG5 (London)PHLDA1
Cancer3DPHLDA1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605335   
Orphanet
DisGeNETPHLDA1
MedgenPHLDA1
Genetic Testing Registry PHLDA1
NextProtQ8WV24 [Medical]
TSGene22822
GENETestsPHLDA1
Target ValidationPHLDA1
Huge Navigator PHLDA1 [HugePedia]
snp3D : Map Gene to Disease22822
BioCentury BCIQPHLDA1
ClinGenPHLDA1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD22822
Chemical/Pharm GKB GenePA33274
Clinical trialPHLDA1
Miscellaneous
canSAR (ICR)PHLDA1 (select the gene name)
Other databasePhosphoSitePlus
Probes
Litterature
PubMed33 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePHLDA1
EVEXPHLDA1
GoPubMedPHLDA1
iHOPPHLDA1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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