BAG1 (BCL2-associated athanogene)

2008-11-01 Samantha L Southern , Victoria Skeen , Ann C Williams. Affiliation

Department of Cellular, Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol,BS8 1TD, UK

Identity

HGNC

BAG1

LOCATION

9p13.3

LOCUSID

573

ALIAS

BAG-1,HAP,RAP46

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

centromere to telomerase orientation; 7 exons.

Transcription

5 alternative transcripts; 1079 nucleotides mRNA.

Proteins

BAG-1 isoforms and their domains. The human BAG-1 gene, located on chromosome 9p12, comprises seven exons which generate an mRNA product of approximately 1.5kb. Three major BAG-1 isoforms are produced from alternative translation start sites within BAG-1 mRNA. The 50kDa BAG-1L isoform is translated from the first in-frame CUG codon by CAP-dependent translation, while BAG-1M and BAG-1S are produced from two downstream AUG codons. BAG-1M is also produced by a CAP-dependent translation mechanism, while BAG-1S is generated by IRES-dependent translation resulting in highest abundance of this short isoform. BAG-1L contains a bipartite nuclear localisation sequence (NLS, purple), the amino-terminal portion of which overlaps with a DNA binding domain (blue). BAG-1M contains a partial NLS, while the NLS is completely absent from BAG-1S. An acidic serine/threonine rich region (green) has been implicated in protein-protein interactions. The ubiquitin-like domain (yellow) and BAG domain (red) are present in all three isoforms.

Description

Three isoforms generated by alternative translation initiation; 50kDa (BAG-1L), 46kDa (BAG-1M) and 36kDa (BAG-1S)(Yang et al., 1998). Each BAG-1 isoform contains a conserved BAG domain and ubiquitin-like domain, with variation in length of their N-terminal sequences.

Expression

Expressed ubiquitously and found to be over-expressed in a number of cancers.

Localisation

The BAG-1 isoforms differ in their subcellular localisation. BAG-1L is predominantly nuclear, BAG-1M is both nuclear and cytoplasmic and BAG-1S is predominantly cytoplasmic (Packham et al., 1997; Takayama et al., 1998; Yang et al., 1998; Brimmell et al., 1999). However, subcellular localisation can be cell type and context dependent, for example in response to heat shock and hormonal stimulation (Schneikert et al., 1999; Zeiner et al., 1999).

Function

Multifunctional protein: Identified as having a role in many different cellular processes including the regulation of apoptosis, proliferation, transcription, proteasome-mediated degradation and a possible role in motility and metastasis (reviewed in Cutress et al., 2003). BAG-1 affects many cellular processes through interaction with a wide variety of cellular proteins, summarised in the table 1.

Table 1. Summary of proteins that interact with BAG-1 and some of the reported cellular functions. BAG-1 associates with a wide range of proteins and through these interactions may have multiple cellular effects, any of which might contribute to cancerous cell phenotypes.

Homology

BAG family of proteins that share a common BAG domain. At present six BAG family proteins have been identified in humans: BAG-1 (Rap46) BAG-2, BAG-3, BAG-4 (sodd), BAG-5 and BAG-6 (BAT3).

Mutations

Note

Unknown

Implicated in

Entity name

Various cancers

Disease

BAG-1 expression is frequently altered in human cancer (Townsend et al., 2003). It has been shown to be over-expressed relative to normal cells in a number of cancers including breast cancer (Tang et al., 1999), colorectal cancer (Kikuchi et al., 2002; Clemo et al. 2008) and human squamous cell carcinoma(Shindoh et al., 2000), endometrial cancer(Moriyama et al., 2004), prostate cancer (Krajewska et al., 2006) and lung cancer (Rorke et al., 2001). Altered expression has been found in pre-malignant lesions (Clemo et al., 2008), implicating a role early in tumour development. BAG-1 has also been suggested to be involved in metastatic disease (Takaoka et al., 1997; Yawata et al., 1998; Hague et al., 2002, reviewed by Sharp et al., 2004).

Prognosis

BAG-1 expression has been shown to be a prognostic factor in a number of cancers. Kikuchi et al (2002) showed in colorectal cancer, that high nuclear BAG-1 expression resulted in a poorer prognosis and a higher risk of metastases. In oesophageal cancer, BAG-1 expression has also been linked to poor prognosis (Takeno et al., 2007). In breast cancer over-expression of BAG-1 has been suggested to be a poor prognostic factor (Krajewski et al., 1999). However, there is conflicting data, with some studies finding increased BAG-1 expression results in a good prognosis (Turner et al., 2001; Nadler et al., 2008), or establishing no link between expression and prognosis (Sjostrom et al., 2002; Tang et al., 2004).

Bibliography

Pubmed ID	Last Year	Title	Authors
12845674	2003	The retinoblastoma protein interacts with Bag-1 in human colonic adenoma and carcinoma derived cell lines.	Arhel NJ et al
8947043	1996	HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death.	Bardelli A et al
15843891	2005	Nuclear BAG-1 expression inhibits apoptosis in colorectal adenoma-derived epithelial cells.	Barnes JD et al
10576663	1999	High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers.	Brimmell M et al
16042572	2005	The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival.	Clemo NK et al
18204076	2008	BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappaB activity.	Clemo NK et al
12902980	2003	The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription.	Cutress RI et al
11676916	2001	Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling.	Demand J et al
9565586	1998	BAG-1L protein enhances androgen receptor function.	Froesch BA et al
16116448	2005	Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells.	Götz R et al
12081206	2002	Deregulated Bag-1 protein expression in human oral squamous cell carcinomas and lymph node metastases.	Hague A et al
12402153	2002	Nuclear BAG-1 expression reflects malignant potential in colorectal carcinomas.	Kikuchi R et al
16482527	2006	Expression of BAG-1 protein correlates with aggressive behavior of prostate cancers.	Krajewska M et al
10732784	1999	Prognostic significance of apoptosis regulators in breast cancer.	Krajewski S et al
9603979	1998	RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis.	Kullmann M et al
11340068	2001	BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation.	Lin J et al
10809723	2000	Distinct isoforms of the cofactor BAG-1 differentially affect Hsc70 chaperone function.	Lüders J et al
9582267	1998	p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1.	Matsuzawa S et al
15297164	2004	BAG-1 expression in normal and neoplastic endometrium.	Moriyama T et al
18430249	2008	Expression patterns and prognostic value of Bag-1 and Bcl-2 in breast cancer.	Nadler Y et al
11329370	2001	Transcriptional activation by the human Hsp70-associating protein Hap50.	Niyaz Y et al
9396724	1997	Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation.	Packham G et al
11494232	2001	Prognostic significance of BAG-1 expression in nonsmall cell lung cancer.	Rorke S et al
10477749	1999	A nuclear action of the eukaryotic cochaperone RAP46 in downregulation of glucocorticoid receptor activity.	Schneikert J et al
15033003	2004	BAG-1 in carcinogenesis.	Sharp A et al
10964051	2000	BAG-1 expression correlates highly with the malignant potential in early lesions (T1 and T2) of oral squamous cell carcinoma.	Shindoh M et al
11895913	2002	The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.	Sjöström J et al
11231577	2001	Bag1-Hsp70 mediates a physiological stress signalling pathway that regulates Raf-1/ERK and cell growth.	Song J et al
9205104	1997	Anti-cell death activity promotes pulmonary metastasis of melanoma cells.	Takaoka A et al
9679980	1998	Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines.	Takayama S et al
17260107	2007	Assessment of clinical outcome in patients with esophageal squamous cell carcinoma using TNM classification score and molecular biological classification.	Takeno S et al
15026618	2004	BAG-1 expression correlates with Bcl-2, p53, differentiation, estrogen and progesterone receptors in invasive breast carcinoma.	Tang SC et al
15474970	2005	BAG-1: a multi-functional pro-survival molecule.	Townsend PA et al
11181661	2001	BAG-1: a novel biomarker predicting long-term survival in early-stage breast cancer.	Turner BC et al
8692945	1996	Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1.	Wang HG et al
9747877	1998	Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells.	Yang X et al
9632144	1998	Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells.	Yawata A et al
8524784	1995	A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning.	Zeiner M et al
10468585	1999	The hsp70-associating protein Hap46 binds to DNA and stimulates transcription.	Zeiner M et al

Other Information

Locus ID:

NCBI: 573
MIM: 601497
HGNC: 937
Ensembl: ENSG00000107262

Variants:

dbSNP: 573
ClinVar: 573
TCGA: ENSG00000107262
COSMIC: BAG1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000107262	ENST00000379704	Q99933
ENSG00000107262	ENST00000379707	F1LLU6
ENSG00000107262	ENST00000473464	A0A0U1RR89
ENSG00000107262	ENST00000473781	C9JYK5
ENSG00000107262	ENST00000488499	C9J9Y9
ENSG00000107262	ENST00000634734	J3QTA2
ENSG00000107262	ENST00000635077	A0A0U1RQD7

Expression (GTEx)

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

Pathway	Source	External ID
Protein processing in endoplasmic reticulum	KEGG	ko04141
Protein processing in endoplasmic reticulum	KEGG	hsa04141
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular response to heat stress	REACTOME	R-HSA-3371556
Regulation of HSF1-mediated heat shock response	REACTOME	R-HSA-3371453

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
15169918	2004	Bag-1 internal ribosome entry segment activity is promoted by structural changes mediated by poly(rC) binding protein 1 and recruitment of polypyrimidine tract binding protein 1.	51
9396724	1997	Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation.	50
24318877	2014	Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.	50
9679980	1998	Expression and location of Hsp70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines.	46
18805052	2008	Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium.	43
17954934	2007	BAG-1 associates with Hsc70.Tau complex and regulates the proteasomal degradation of Tau protein.	39
18684711	2008	Functional divergence between co-chaperones of Hsc70.	38
20675402	2010	Bag1 directly routes immature BCR-ABL for proteasomal degradation.	28
14517289	2003	The cochaperone Bag-1L enhances androgen receptor action via interaction with the NH2-terminal region of the receptor.	27

Citation

Samantha L Southern ; Victoria Skeen ; Ann C Williams.

BAG1 (BCL2-associated athanogene)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

Online version: http://atlasgeneticsoncology.org/gene/742/bag1id742ch9p13