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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

Other aliasDT1P1B11
PHRIP
TDAG51
LocusID (NCBI) 22822
Atlas_Id 41707
Location 12q21.2  [Link to chromosome band 12q21]
Location_base_pair Starts at and ends at bp from pter
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
Cards
AtlasPHLDA1ID41707ch12q15.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)22822
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Other databasePhosphoSitePlus
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:47:25 CEST 2018

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