GADD45A (growth arrest and DNA-damage-inducible, alpha)

2014-06-01   Sirma Damla User  , Mesut Muyan  

Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Identity

HGNC
GADD45A
LOCATION
1p31.3
IMAGE
Atlas Image
LOCUSID
1647
ALIAS
DDIT1,GADD45
FUSION GENES
Show Gene Fusions

Abstract

Growth Arrest and DNA-damage-inducible, alpha (GADD45α) is a member of the GADD family proteins that also include GADD45β and GADD45γ. The highly conserved GADD45 proteins are small (18 kDa) and primarily localized in the nucleus. The GADD45 proteins acting as sensors of environmental and physiological stress interact with and\/or modulate the activities of partner proteins involved in cell cycle, cell survival, apoptosis, maintenance of genomic stability and DNA repair. GADD45 proteins also act as sensors of oncogenic stress in the initiation of tumors and in tumor responses to different therapeutics. The expression of GADD45α in response to DNA damage is mediated by p53-dependent and p53-independent mechanisms, the latter which involves Wilms tumor 1 (WT1) protein. GADD45α subsequently inhibits G2\/M transition of cell cycle and induces apoptosis. GADD45α also has a role in DNA-demethylation to promote genome stability. In many malignancies, GADD45α levels are down-regulated, likely allowing tumor cells to escape from senescence and apoptosis. Novel approaches are therefore being developed to regulate GADD45α levels to combat malignancies.

DNA/RNA

Atlas Image
Human GADD45α located on chromosome 1 is on the forward strand. It consists of four exons represented as boxes and introns shown as lines. Darker grey boxes indicate the open reading frame (ORF) of 498 base pairs (bp). The first methionine (ATG) and the stop codon (TGA) of ORF are marked. The length of each exon and intron is shown in base pairs.

Description

The human GADD45α is localized on chromosome 1 and comprises four exons (NCBI, 2014).

Transcription

Depending on the splicing of the GADD45α pre-mRNA, there are three mRNA variants.

Pseudogene

Homologous sequence on chromosome 12q may be a retro-pseudogene (Papathanasiou et al., 1991).

Proteins

Note

Based on mRNA sequences, it is predicted that there are three isoforms of GADD45α protein (NCBI, 2014). While the isoform 1 utilizes 498 bp ORF encoding 165 amino acids (aa)-long protein (protein ID: NP_001915.1), the absence of the second in-frame exon in the isoform 2 results in a 396 bp ORF giving rise to a 131 aa-long protein (protein ID: NP_001186670.1). In the isoform 3, the second and third exons partially exist forming a 183 bp mRNA that encodes a 60 aa-long protein (protein ID: NP_001186671.1).

Description

GADD45α protein is a member of the GADD family that includes GADD45β and GADD45γ. Forming a homodimer as well as heterodimers with other family members, GADD45α is involved in the maintenance of genomic integrity, growth arrest and apoptosis (Rosemary Siafakas and Richardson, 2009; Sytnikova et al., 2011) through interactions with various proteins including Cdc2 protein kinase, p21Waf1/Cip1 protein, core histone proteins, proliferating cell nuclear antigen (PCNA) and MTK/MEKK4 (Zerbini and Libermann, 2005; Zhan, 2005; Rosemary Siafakas and Richardson, 2009; Johnson et al., 2013). GADD45α also acts as an RNA binding protein (Sytnikova et al., 2011). Ubiquitination appears to be involved in the turnover of GADD45α (Leung et al., 2001).

Expression

Protein levels of GADD45α varies during the cell cycle, the highest being in G1 phase and the lowest in S phase (Zhan, 2005; Rosemary Siafakas and Richardson, 2009). The expression of GADD45α is regulated by p53-dependent and p53-independent mechanisms. The p53-dependent pathway involves the direct binding of p53 to a cognate response element located on the third intron of GADD45α. Whereas, in the p53-independent signaling route, p53 modulates GADD45α expression by interacting with WT1, a transcription factor and a tumor suppressor, bound on GC-rich motifs of the GADD45α promoter (Zhan, 2005; Johnson et al., 2013). Rapid and transient expression of GADD45α can be induced by DNA damaging agents including UV (p53-independent), ionizing radiation (p53-dependent), methylmethane sulfonate (MMS), nitrogen mustard, melphalan, hydrogen peroxide and hypoxia as well as by the withdrawal of growth factors (Hollander and Fornace, 2002; Zhan, 2005; Rosemary Siafakas and Richardson, 2009). GADD45α expression is also activated by breast cancer 1, early onset, (BRCA1) in various cell lines (Harkin et al., 1999).

Localisation

GADD45α, as other members of GADD family proteins, is predominantly localized in the nucleus (Zhan, 2005; Rosemary Siafakas and Richardson, 2009). In glioblastoma and breast tumors, GADD45α is also observed to localize in the cytoplasm (Reddy et al., 2008; Tront et al., 2013).

Function

The maintenance of genome integrity is essential to prevent the development of cancer, which is associated with genomic instability. GADD45α plays an important role in maintaining genomic integrity by promoting nucleotide-excision repair (NER), cell cycle arrest and apoptosis (Hollander and Fornace, 2002; Barreto et al., 2007; Sytnikova et al., 2011). GADD45α mediates NER by binding to repair endonuclease xeroderma pigmentosum G (XPG) protein (Hollander and Fornace, 2002; Barreto et al., 2007; Sytnikova et al., 2011). While the disruption of Cdc2/Cyclin B1 interactions by GADD45α is critical for the blockage of G2/M transition (Zhan et al., 1999; Rosemary Siafakas and Richardson, 2009), the activation of c-Jun N-terminal kinase (JNK) as a result of the interaction of GADD45α with mitogen-activated protein three kinase (MTK1) induces apoptosis (Zerbini and Libermann, 2005). GADD45α is also reported to repress cell migration and invasion by suppressing β-catenin signaling through stress-mediated p38 mitogen activated protein kinase (MAPK) pathway (Hildesheim et al., 2004).

Homology

The human GADD45α shows 90% aa identity to GADD45α of other species including rhesus monkey, domestic cat, hamster, mouse and rat (Rosemary Siafakas and Richardson, 2009). In addition, there is a nearly 50% aa identity among GADD45α and other GADD45 proteins (Rosemary Siafakas and Richardson, 2009). The RNA-binding domain of GADD45α displays high aa homology to many RNA binding proteins that includes ribosomal proteins L7a, S12 and L30e (Sytnikova et al., 2011; Tian and Locker, 2013).

Implicated in

Entity name
Colorectal carcinoma
Note
In primary colorectal carcinoma tissue samples grouped according to tumor staging (group 1: restricted to gut; group 2: restricted to gut but signs of malignancy on lymph nodes are present; group 3: in addition to group 2 characteristics, metastasis to distant tissue is present), it was observed that GADD45α expression decreases as staging increases. Whereas, GADD45α expression in close proximity or distant tissues remains unchanged (Štorcelová et al., 2013).
Entity name
Breast cancer
Note
Intracellular level of GADD45α assessed by immunocytochemistry is reported to positively correlate with the presence of estrogen and progesterone receptors in primary breast cancer samples (Tront et al., 2013). It appears that GADD45α levels are higher in Luminal A (ER+, PR+, HER2-) and Luminal B (ER+, PR+, HER2+) subgroups of tumors than HER2+ (HER2+, ER-,PR-) and Triple Negative (ER-, PR-, HER2-) subgroups (Tront et al., 2013).
Entity name
Gastric cardia adenocarcinoma
Note
Relative mRNA expression evaluated by qPCR of gastric cardia adenocarcinoma (GCA) samples suggests that the expression of GADD45α is repressed compared to that of neighboring normal tissue samples. Based on TNM staging, GADD45α mRNA levels were found to be higher in Stage I and Stage II patient samples than Stage III and Stage IV patient samples. Higher degree of methylation of the GADD45α gene promoter appears to be one reason for the decreased expression of GADD45α in GCA. There were no other correlation between GADD45α mRNA levels and clinicopathological characteristics (Guo et al., 2013).
Entity name
Glioblastoma
Note
In diffuse-infiltrating astrocytomas, the expression of GADD45α assessed by qPCR shows variations depending on tumor grading. It appears that GADD45α is expressed at higher levels in glioblastoma (GBM; WHO grade IV) compared to astrocytoma (DA; WHO grade II) or to anaplastic astrocytoma (AP; WHO grade III) (Reddy et al., 2008).

Article Bibliography

Pubmed IDLast YearTitleAuthors
172684712007Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.Barreto G et al
236161232013Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma.Guo W et al
103678871999Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.Harkin DP et al
146474292004Gadd45a regulates matrix metalloproteinases by suppressing DeltaNp63alpha and beta-catenin via p38 MAP kinase and APC complex activation.Hildesheim J et al
122142532002Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a.Hollander MC et al
234760082013The involvement of WT1 in the regulation of GADD45a in response to genotoxic stress.Johnson D et al
114448392001PKCdelta-dependent deubiquitination and stabilization of Gadd45 in A431 cells overexposed to EGF.Leung CH et al
19902621991Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.Papathanasiou MA et al
184833632008Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis.Reddy SP et al
187603772009Growth arrest and DNA damage-45 alpha (GADD45alpha).Rosemary Siafakas A et al
240620752013Expression of cell cycle regulatory factors hus1, gadd45a, rb1, cdkn2a and mre11a correlates with expression of clock gene per2 in human colorectal carcinoma tissue.Štorcelová M et al
212491302011Gadd45a is an RNA binding protein and is localized in nuclear speckles.Sytnikova YA et al
241044742013Gadd45 in the liver: signal transduction and transcriptional mechanisms.Tian J et al
237061182013Gadd45a levels in human breast cancer are hormone receptor dependent.Tront JS et al
156138502005Life and death in cancer. GADD45 alpha and gamma are critical regulators of NF-kappaB mediated escape from programmed cell death.Zerbini LF et al
103622601999Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45.Zhan Q et al
156037582005Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage.Zhan Q et al

Other Information

Locus ID:

NCBI: 1647
MIM: 126335
HGNC: 4095
Ensembl: ENSG00000116717

Variants:

dbSNP: 1647
ClinVar: 1647
TCGA: ENSG00000116717
COSMIC: GADD45A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000116717ENST00000370985P24522
ENSG00000116717ENST00000370986P24522
ENSG00000116717ENST00000617962A0A087WZQ0
ENSG00000116717ENST00000648742A0A3B3ITF9
ENSG00000116717ENST00000650283A5JUZ3

Expression (GTEx)

0
50
100
150
200
250
300
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
ApoptosisKEGGko04210
MAPK signaling pathwayKEGGhsa04010
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
ApoptosisKEGGhsa04210
FoxO signaling pathwayKEGGhsa04068
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Transcription of Cell Cycle GenesREACTOMER-HSA-6791312
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle ArrestREACTOMER-HSA-6804114

References

Pubmed IDYearTitleCitations
385792862024Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.0
386822082024Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.0
385792862024Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.0
386822082024Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.0
365113432023Growth arrest and DNA damage-inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha.5
366171742023BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis†.2
370305352023Interleukin-23 mediates the reduction of GADD45a expression to attenuate oxidative stress-induced cellular senescence in human fibroblasts.0
370597452023Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers.0
378158642023GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.2
379461772023IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A.1
365113432023Growth arrest and DNA damage-inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha.5
366171742023BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis†.2
370305352023Interleukin-23 mediates the reduction of GADD45a expression to attenuate oxidative stress-induced cellular senescence in human fibroblasts.0
370597452023Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers.0
378158642023GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.2

Citation

Sirma Damla User ; Mesut Muyan

GADD45A (growth arrest and DNA-damage-inducible, alpha)

Atlas Genet Cytogenet Oncol Haematol. 2014-06-01

Online version: http://atlasgeneticsoncology.org/gene/339/gadd45a-(growth-arrest-and-dna-damage-inducible-alpha)