CRYAB (crystallin, alpha B)

2009-03-01   Aysegul Ilhan , Ludwig Wagner , Wolfgang Gartner 

Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Austria

Identity

HGNC
LOCATION
11q23.1
LOCUSID
ALIAS
CMD1II,CRYA2,CTPP2,CTRCT16,HEL-S-101,HSPB5,MFM2
FUSION GENES

DNA/RNA

Description

Crystallins are a highly conserved protein family consisting of three classes, alpha, beta and gamma. The alpha crystallins are divided into two groups according to their acidic as well as basic character, namely A and B. The genes encoding the alpha crystallins A and B are located at chromosome 11 and 21, respectively. The hamster alpha-B crystallin (CRYAB) gene, which is highly homologous to that of humans, was cloned at first by Quax-Jeuken and it was demonstrated that the coding region of CRYAB consists of three exons (Quax-Jeuken et al., 1985).

Transcription

CRYAB was primarily found to be expressed in the lens. At the mRNA level Dubin and his group were the first to detect CRYAB expression in several other tissues such as the lung, heart, skeletal muscle, kidney and to a lower extent within the brain and spleen (Dubin et al., 1989).

Proteins

Description

CRYAB encodes a 175 amino acid long protein with a molecular weight of 22kDa. Although the three-dimensional structure of CRYAB has not been resolved yet, the crystal structures of closely related other members of the heat shock protein family are available. This provided the assumption that CRYAB is composed of a highly conserved "alpha crystallin core" domain consisting of about 80 to 100 residues with a beta-sandwich structure (Ghosh et al., 2005).

Expression

CRYAB was initially found in the vertebrate lens. Iwaki and his group demonstrated CRYAB expression within heart, skeletal muscles, striated muscle, sciatic nerve, kidney and placenta by immunohistochemistry as well as immunoblotting and northern analyses (Iwaki et al., 1990). Furthermore, CRYAB was found to be expressed in several human neoplasms.

Localisation

CRYAB exhibits mainly a cytosolic distribution. However, nuclear localisation with speckled intranuclear formations in various types of unstressed cells was also reported (van den et al., 2003).

Function

CRYAB as well as alpha-A crystallin contribute to ~35% of all vertebrate lens proteins. Therefore, it was firstly suggested that these proteins might be responsible for the refractory index of the eye and for maintaining lens transparency. However, the high abundance of CRYAB in tissues other than the lens and its high homology to heat shock proteins suggested that CRYAB might also represent a small heat shock protein with the potential to exert molecular chaperone function. This suggestion was strengthened by Klemenz et al. by showing heat shock inducability of CRYAB on the promoter level (Klemenz et al., 1991). Basing on the potential of heat shock proteins to bind to unfolded and denatured proteins, thus maintaining a less non-specific protein aggregation, a potential role of CRYAB in inclusion body formation in the course of several neurodegenerative diseases such as Alexander disease (Iwaki et al., 1993), Alzheimers disease (Shinohara et al., 1993), Creutzfeldt-Jacob disease (Kato et al., 1992) and Parkinsons disease (Iwaki et al., 1992) has been suggested. Furthermore CRYAB was found to serve as an auto-antigen in multiple sclerosis (van Noort et al., 1995) and it was shown that small heat shock proteins such as CRYAB are involved in the promotion of prolonged survival of cancer cells by inhibiting apoptosis (Kamradt et al., 2001).

Homology

CRYAB exhibits a high homology of 56% to alpha-A-crystallin. Moreover, additional homologies to several other heat shock proteins were demonstrated (Wistow, 1985).

Mutations

Note

Until now, there are two known mutations within the CRYAB gene with potential impact on human pathologies. Vicart and his group found a missense mutation of R120G within the CRYAB gene, which was associated with desmin-related myopathy (Vicart et al., 1998). Furthermore a deletion mutation within exon 3, 450delA, which results in an aberrant protein, was found to be related to dominant posterior congenital cataract in humans (Berry et al., 2001).

Implicated in

Entity name
Breast cancer
Note
It was reported that CRYAB expression is strongly associated with lymph node metastasis in breast cancer (Chelouche-Lev et al., 2004). This result was further supported by the high abundance of CRYAB in basal like breast carcinoma, which represents a subgroup of breast cancers with bad prognosis and high metastatic potential (Moyano et al., 2006). Furthermore, this research group demonstrated activation of the MEK/ERK pathway through CRYAB over-expression in immortalized human mammary epithelial cells, which lead to increased cell migration and invasion. This effect could be entirely suppressed using MEK/ERK inhibitors.
Entity name
Renal cell carcinoma
Note
Up-regulation of CRYAB expression was found in cultured renal cell carcinoma cells as well as in tissues derived from renal cell carcinomas (Shi et al., 2004). This finding was further confirmed by another research group using protein chip and immunohistochemistry analyses (Holcakova et al., 2008).
Entity name
Brain tumours
Note
Expression of CRYAB within malignant brain tumours such as astrocytomas, oligodendrogliomas and glioblastoma multiforme (GBM) was reported (Iwaki et al., 1991; Aoyama et al., 1993; Shinohara et al., 1993). Moreover, it was demonstrated that chemotherapy induces an increased expression of CRYAB in neuroblastomas (Ishiguro et al., 1997). Comparative proteomic studies on human low grade astrocytomas and GBM showed a significant higher expression of CRYAB within the GBM (Odreman et al., 2005).
Entity name
Anaplastic thyroid carcinoma
Note
Mineva showed differential regulation of CRYAB and the closely related heat shock protein 27-1 (HSP27-1) within the highly malignant anaplastic thyroid carcinomas (ATC). Whereas CRYAB expression was found to be down-regulated, HSP27-1 was considerably expressed within ATC (Mineva et al., 2005). Analyses of the CRYAB promotor region including tumor associated methylation analysis as well as CRYAB promoter specific trasncription factor analysis lead to the suggestion that this might be due to tumor specific transcription factor and promoter methylation patterns.
Entity name
Buccal squamous carcinoma
Note
This type of carcinoma, which is mostly seen in central and southeast Asia, is characterized by a considerably aggressive course. Chen and his group performed a proteomic assay in order to define the expression pattern of cancer-related proteins within this tumor entity. Similar to the anaplastic thyroid carcinomas, CRYAB was found to be underrepresented, whereas several other proteins involved in heat shock responses and anti-oxidative processes were up-regulated (Chen et al., 2004).
Entity name
Head and neck cancer
Note
In consistence with findings of breast cancer research, a high extent of CRYAB expression was found to be a strong predictive marker for short survival rates of patients suffering from head and neck cancer (Chin et al., 2005). However, an investigation of head and neck squamous cell carcinoma did not reveal a significant association between patient survival and CRYAB expression (Boslooper et al., 2008).
Entity name
Hepatocellular carcinoma
Note
The CRYAB gene was found to be highly expressed in a subgroup of hepatocellular carcinomas, which was associated with declined survival rates (Tang et al., 2009). It was suggested that CRYAB might serve as a prognostic marker within hepatocellular carcinomas.

Bibliography

Pubmed IDLast YearTitleAuthors
82445721993Expression of alpha B-crystallin in human brain tumors.Aoyama A et al
115773722001Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans.Berry V et al
186047372008The clinicopathological roles of alpha-B-crystallin and p53 expression in patients with head and neck squamous cell carcinoma.Boslooper K et al
151977942004alphaB-crystallin as a marker of lymph node involvement in breast carcinoma.Chelouche-Lev D et al
152741412004Proteomics of buccal squamous cell carcinoma: the involvement of multiple pathways in tumorigenesis.Chen J et al
159955132005Alpha B-crystallin, a new independent marker for poor prognosis in head and neck cancer.Chin D et al
27254881989Expression of the murine alpha B-crystallin gene is not restricted to the lens.Dubin RA et al
162742332005Interactive domains for chaperone activity in the small heat shock protein, human alphaB crystallin.Ghosh JG et al
184091512008Identification of alphaB-crystallin, a biomarker of renal cell carcinoma by SELDI-TOF MS.Holcakova J et al
91421991997Chemotherapy-induced expression of alpha B-crystallin in neuroblastoma.Ishiguro Y et al
83936181993Alpha B-crystallin and 27-kd heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers.Iwaki T et al
22941481990Cellular distribution of alpha B-crystallin in non-lenticular tissues.Iwaki T et al
17391281992Accumulation of alpha B-crystallin in central nervous system glia and neurons in pathologic conditions.Iwaki T et al
112741392001The small heat shock protein alpha B-crystallin negatively regulates cytochrome c- and caspase-8-dependent activation of caspase-3 by inhibiting its autoproteolytic maturation.Kamradt MC et al
13323651992Ultrastructural and immunohistochemical studies on ballooned cortical neurons in Creutzfeldt-Jakob disease: expression of alpha B-crystallin, ubiquitin and stress-response protein 27.Kato S et al
20239141991Alpha B-crystallin is a small heat shock protein.Klemenz R et al
161847622005Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing.Mineva I et al
163954082006AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer.Moyano JV et al
159527162005Proteomic studies on low- and high-grade human brain astrocytomas.Odreman F et al
38620981985Complete structure of the alpha B-crystallin gene: conservation of the exon-intron distribution in the two nonlinked alpha-crystallin genes.Quax-Jeuken Y et al
151083292004Differential protein profiling in renal-cell carcinoma.Shi T et al
82773361993Alpha B crystallin and HSP28 are enhanced in the cerebral cortex of patients with Alzheimer's disease.Shinohara H et al
189929122009Expression and prognostic significance of the alpha B-crystallin gene in human hepatocellular carcinoma.Tang Q et al
97315401998A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.Vicart P et al
75964141995The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis.van Noort JM et al
128372812003Nuclear speckle localisation of the small heat shock protein alpha B-crystallin and its inhibition by the R120G cardiomyopathy-linked mutation.van den IJssel P et al

Other Information

Locus ID:

NCBI: 1410
MIM: 123590
HGNC: 2389
Ensembl: ENSG00000109846

Variants:

dbSNP: 1410
ClinVar: 1410
TCGA: ENSG00000109846
COSMIC: CRYAB

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000109846ENST00000227251P02511
ENSG00000109846ENST00000227251V9HW27
ENSG00000109846ENST00000525823A0A024R3B9
ENSG00000109846ENST00000526167E9PNH7
ENSG00000109846ENST00000526180P02511
ENSG00000109846ENST00000526180V9HW27
ENSG00000109846ENST00000527899P02511
ENSG00000109846ENST00000527899V9HW27
ENSG00000109846ENST00000527950P02511
ENSG00000109846ENST00000527950V9HW27
ENSG00000109846ENST00000528628E9PS12
ENSG00000109846ENST00000528961A0A024R3B9
ENSG00000109846ENST00000529647E9PJL7
ENSG00000109846ENST00000531198P02511
ENSG00000109846ENST00000531198V9HW27
ENSG00000109846ENST00000533280A0A024R3B9
ENSG00000109846ENST00000533475P02511
ENSG00000109846ENST00000533475V9HW27
ENSG00000109846ENST00000533879P02511
ENSG00000109846ENST00000533879V9HW27
ENSG00000109846ENST00000533971E9PRA8
ENSG00000109846ENST00000616970P02511
ENSG00000109846ENST00000616970V9HW27
ENSG00000109846ENST00000650687P02511
ENSG00000109846ENST00000650687V9HW27
ENSG00000109846ENST00000651164P02511
ENSG00000109846ENST00000651164V9HW27
ENSG00000109846ENST00000651650A0A024R3B9

Expression (GTEx)

0
500
1000
1500
2000

Pathways

PathwaySourceExternal ID
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
175686992007Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination.164
176932542007Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.164
170819872006Phosphorylation-dependent ubiquitination of cyclin D1 by the SCF(FBX4-alphaB crystallin) complex.152
163954082006AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer.100
208024872010Solid-state NMR and SAXS studies provide a structural basis for the activation of alphaB-crystallin oligomers.85
121402792002The small heat shock protein alpha B-crystallin negatively regulates apoptosis during myogenic differentiation by inhibiting caspase-3 activation.78
126007162003Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model.78
115773722001Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans.74
156536862005The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3.74
188103222009Crystallin proteins and amyloid fibrils.69

Citation

Aysegul Ilhan ; Ludwig Wagner ; Wolfgang Gartner

CRYAB (crystallin, alpha B)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/40156/cryab