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

2014-01-01   Maria 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

Identity

HGNC
LOCATION
12q21.2
LOCUSID
ALIAS
DT1P1B11,PHRIP,TDAG51
FUSION GENES

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.

Proteins

Atlas Image
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

Entity name
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 name
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 name
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 name
Colon cancer
Note
Altered PHLDA1 expression has been shown to be associated with the process of intestinal tumorigenesis (Sakthianandeswaren et al., 2011).
Entity name
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 name
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 name
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

Pubmed IDLast YearTitleAuthors
237489152013Expression of PAR-4 and PHLDA1 is prognostic for overall and disease-free survival in oral squamous cell carcinomas.Coutinho-Camillo CM et al
105942391999A novel pleckstrin homology-related gene family defined by Ipl/Tssc3, TDAG51, and Tih1: tissue-specific expression, chromosomal location, and parental imprinting.Frank D et al
236863692013Deficiency of TDAG51 protects against atherosclerosis by modulating apoptosis, cholesterol efflux, and peroxiredoxin-1 expression.Hossain GS et al
218079362011PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer.Johnson EO et al
108949222000Assignment of the human PHLDA1 gene to chromosome 12q15 by radiation hybrid mapping.Kuske MD et al
186417962008Transcriptional up-regulation of PHLDA1 by 17beta-estradiol in MCF-7 breast cancer cells.Marchiori AC et al
172115332007Down-regulation of PHLDA1 gene expression is associated with breast cancer progression.Nagai MA et al
123845582002Identification of the human PHLDA1/TDAG51 gene: down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation.Neef R et al
150020432004Regulation of T-cell death-associated gene 51 (TDAG51) expression in human T-cells.Oberg HH et al
163954072006Characterization and isolation of stem cell-enriched human hair follicle bulge cells.Ohyama M et al
86737051996A novel gene product that couples TCR signaling to Fas(CD95) expression in activation-induced cell death.Park CG et al
215583892011PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis.Sakthianandeswaren A et al
213522652011Follicular stem cell marker PHLDA1 (TDAG51) is superior to cytokeratin-20 in differentiating between trichoepithelioma and basal cell carcinoma in small biopsy specimens.Sellheyer K et al
150376192004TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival.Toyoshima Y et al
178702362007TDAG51 in the anterior temporal neocortex of patients with intractable epilepsy.Xi ZQ et al

Other Information

Locus ID:

NCBI: 22822
MIM: 605335
HGNC: 8933
Ensembl: ENSG00000139289

Variants:

dbSNP: 22822
ClinVar: 22822
TCGA: ENSG00000139289
COSMIC: PHLDA1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000139289ENST00000266671Q8WV24
ENSG00000139289ENST00000602540R4GND3
ENSG00000139289ENST00000619060Q8WV24

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Interaction between PHLDA1 and AURKAREACTOMER-HSA-8854521

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
123845582002Identification of the human PHLDA1/TDAG51 gene: down-regulation in metastatic melanoma contributes to apoptosis resistance and growth deregulation.31
218079362011PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer.28
150376192004TDAG51 mediates the effects of insulin-like growth factor I (IGF-I) on cell survival.26
172115332007Down-regulation of PHLDA1 gene expression is associated with breast cancer progression.26
215583892011PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis.23
249545072015PHLDA1 expression is controlled by an estrogen receptor-NFκB-miR-181 regulatory loop and is essential for formation of ER+ mammospheres.21
225926412012TDAG51 mediates epithelial-to-mesenchymal transition in human proximal tubular epithelium.15
242700132014Differential susceptibility to hydrogen sulfide-induced apoptosis between PHLDA1-overexpressing oral cancer cell lines and oral keratinocytes: role of PHLDA1 as an apoptosis suppressor.11
294902812018PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer.9
150020432004Regulation of T-cell death-associated gene 51 (TDAG51) expression in human T-cells.8

Citation

Maria Aparecida Nagai

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

Atlas Genet Cytogenet Oncol Haematol. 2014-01-01

Online version: http://atlasgeneticsoncology.org/gene/41707/phlda1