BCLAF1 (BCL2-associated transcription factor 1)

2011-06-01   John Peter McPherson 

Department of Pharmacology, Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8 Canada

Identity

HGNC
LOCATION
6q23.3
LOCUSID
ALIAS
BTF,bK211L9.1
FUSION GENES

DNA/RNA

Description

The BCLAF1 gene is composed of 13 exons and spans 32989 bases.

Transcription

Two transcripts 5 kb and 3 kb in length are predominantly detected, however additional variant transcripts have been described with alternative promoters, cassette exons and polyadenylation sites.

Pseudogene

None identified.

Proteins

Atlas Image
Protein domains in BCLAF1L and BCLAF1S isoforms.

Description

At least 4 isoforms are generated by alternative splicing. Two predominant BCLAF1 forms were initially described: a longer isoform 920 amino acids in length with a predicted molecular mass of 106 kDa, and a smaller isoform missing 49 amino acids (residues 797-846) with a predicted molecular mass of 101 kDa (Kasof et al., 1999). Residues 110-126 exhibit 88% homology to the bZIP DNA binding domain (Kasof et al., 1999). Residues 522-531 exhibit 80% homology to the Myb DNA binding domain (Kasof et al., 1999). Functional evidence for both of these domains remains to be shown. The N-terminal region (residues 3-161) of BCLAF1 is arginine- and serine-rich (RS domain). The C-terminal region (residues 512-913) is 59% similar to the C-terminal region of thyroid hormone receptor associated protein 3 (THRAP3/TRAP150).

Expression

BCLAF1 is ubiquitously expressed, with high steady-state mRNA levels in skeletal muscle, haematopoietic cells, and various other cell lineages (Kasof et al., 1999; McPherson et al., 2009). Steady-state levels of BCLAF1 protein fluctuate in a temporal and cell-lineage dependent fashion during development (McPherson et al., 2009).

Localisation

Bclaf1 is concentrated in punctate foci interspersed through the nucleus. In the presence of E19K and conditions which trigger apoptosis, the nuclear distribution of Bclaf1 appears to concentrate at the nuclear periphery or envelope (Kasof et al., 1999; Haraguchi et al., 2004).
Bclaf1 was identified as a protein component of interchromatin granular clusters, subnuclear structures that appear to serve as repositories for pre-mRNA splicing factors (Misteli and Spector, 1998; Sutherland et al., 2001; Saitoh et al., 2004).

Function

The exact molecular function of BCLAF1 remains to be defined. BCLAF1 was originally identified as having properties of a death-inducing transcriptional repressor (Kasof et al., 1999). Several subsequent studies have expanded on the link between BCLAF1, transcription and apoptosis. Depletion of BCLAF1 was reported to render cells resistant to ceramide-induced apoptosis (Renert et al., 2009). Protein kinase C delta-mediated transactivation of p53 transcription has been shown to occur through the stimulation of BCLAF1 to co-occupy a core promoter element in the TP53 promoter (Liu et al., 2007). A role for Bclaf1 in lung development and T cell homeostasis was demonstrated in Bclaf1-deficient mice (McPherson et al., 2009). Bclaf1 was shown to be required for the proper spatial and temporal organization of smooth muscle lineage cells during the saccular stage of lung development. Bclaf1 was also shown to be critical for T cell activation. The phenotype of these mice could not be explained by a defect in apoptosis, furthermore Bclaf1-deficient cells displayed no defect in cell death following exposure to various apoptotic stimuli.
Recent studies have implicated BCLAF1 in processes linked to RNA metabolism. BCLAF1 contains an RS domain, a feature of many factors that facilitate pre-mRNA splicing and mRNA processing. BCLAF1 was found to be a component of ribonucleoprotein complexes (Merz et al., 2007; Sarras et al., 2010). Bclaf1-deficient cells were found to exhibit altered preferences for alternative splicing of a model substrate (Sarras et al., 2010). BCLAF1 was found associated with SkIP, TRAP150 and Pinin in a complex known as SNIP1. SNIP1 was found to regulate cyclin D1 mRNA processing by facilitating the recruitment of the RNA processing factor U2AF65 to cyclin D1 mRNA (Bracken et al., 2008).
BCLAF1 has been shown to complex with the RNA export factor TAP/NXF1 (Sarras et al., 2010). This property has also recently been reported for TRAP150, a protein showing structural similarity to BCLAF1 that also is found in ribonucleoprotein complexes (Lee et al., 2010). TRAP150 has been shown to promote pre-mRNA splicing of reporter substrates and promotes mRNA decay in a manner that is independent of nonsense-mediated decay of mRNA (Lee et al., 2010).

Regulation
Sirt1 has been shown to exert transcriptional control of BCLAF1 at the promoter level (Kong et al., 2011). Sirt1 was found to form a complex with the histone acetyltransferase p300 and NF-kB transcription factor Rel-A, bind the BCLAF1 promoter and suppress BCLAF1 transcription via H3K56 deacetylation (Kong et al., 2011).
BCLAF1 protein levels fluctuate according to cell cycle position, with levels highest during the G1 phase, but lower during S and G2 phases (Bracken et al., 2008). BCLAF1 protein levels also fluctuate in a cell-lineage and temporal manner during differentiation of certain tissues and organs (McPherson et al., 2009).
Several studies have determined that Bclaf1 is extensively phosphorylated, although the functional significance of this modification is unclear. BCLAF1 has been proposed as a substrate of GSK-3 kinase (Linding et al., 2007). Vasopressin action in kidney cells has been reported to simulate BCLAF1 phosphorylation (Hoffert et al., 2006).
BCLAF1 has been shown to be one of the cellular targets for microRNAs (miRNAs) encoded by Kaposis sarcoma-associated herpesvirus (KSHV). KSHV triggers certain acquired immune deficiency syndrome-related malignancies such as Kaposis sarcoma, primary effusion lymphoma and variants of multicentric Castleman disease. A miRNA cluster within the KSHV genome is expressed during viral latency. During induction of lytic KSHV growth, inhibition of miRNAs was associated with increased BCLAF1 expression and decreased KSHV virion production (Ziegelbauer et al., 2009).

Interactions
E1B 19K. By yeast two-hybrid analysis, BCLAF1 was shown to directly interact with adenoviral E1B 19K via a BH3 domain and another region immediately adjacent to BH3 in E1B 19K (Kasof et al., 1999). In vitro binding assays reported BCLAF1 associates with BCL-2 and BCL2L1.
emerin. By yeast-two hybrid analysis and microtiter well binding assays, BCLAF1 was shown to directly interact with emerin, a nuclear membrane protein. Mutations that result in a loss of functional emerin cause X-linked recessive Emery-Dreifuss muscular dystrophy. The residues of emerin required for binding to BCLAF1 mapped to two regions that flank its lamin-binding domain. Two disease-causing mutations in emerin, S54F and Delta95-99, disrupted binding to BCLAF1. BCLAF1 and emerin were observed to co-localize in the vicinity of the nuclear envelope following induction of apoptosis by Fas antibody (Haraguchi et al., 2004).
MAN1. The C-terminal domain of MAN1, a nuclear inner membrane protein that inhibits Smad signaling downstream of transforming growth factor beta, was observed to bind BCLAF1, as well as the transcriptional regulators GCL, and barrier-to-autointegration factor (BAF) (Mansharamani and Wilson, 2005).
Factors that participate in RNA metabolism. BCLAF1 and TRAP150 have been identified to be protein components of ribonucleoprotein complexes that participate in pre-mRNA splicing and other mRNA processing events (Merz et al., 2007; Sarras et al., 2010; Lee et al., 2010). Both BCLAF1 and TRAP150 have been reported to reside in protein complexes that contain the mRNA export factor NXF1/TAP (Sarras et al., 2010; Lee et al., 2010). Both BCLAF1 and TRAP150, together with Pinin and SkIP, have been found in a protein complex that regulates cyclin D1 mRNA stability.

Homology

BCLAF1 shares amino acid similarity (48% overall identity) with TRAP150 in their C-terminal domains. Both proteins also contain RS-rich tracts within their N-termini (Lee et al., 2010).

Mutations

Note

BCLAF1 is located at chromosome 6q23 , a region that has been reported to exhibit a high frequency of deletions in tumours, such as lymphomas and leukemias. BCLAF1 has observed to be absent in Raji cells, derived from Burkitts lymphoma, which has deletions in 6q (Kasof et al., 1999). A role for the loss of BCLAF1 in neoplastic transformation remains to be determined and may be coincidental.

Implicated in

Entity name
X-linked recessive Emery-Dreifuss muscular dystrophy
Note
Bclaf1 has also recently been identified as a binding partner for emerin, a nuclear membrane protein that is mutated in X-linked recessive Emery-Dreifuss muscular dystrophy. Disease mutations in emerin were found to disrupt the interaction of emerin with BCLAF1 (Haraguchi et al., 2004).
Disease
Emerin is encoded by the EMD gene located on human X-chromosome, which when mutated, gives rise to the X-linked form of Emery-Dreifuss muscular dystrophy (Bione et al., 1994). Emerin is a lamin A/C binding protein that participates in nuclear envelope mechanics which impact chromosome segregation, gene expression and muscle differentiation (Liu et al., 2003; Frock et al., 2006).
Entity name
Choroid plexus papillomas
Note
Up-regulation of BCLAF1 was observed in seven cases of choroid plexus papilloma cells compared to eight cases of normal choroid plexus epithelial cells (Hasselblatt et al., 2009).
Disease
Choroid plexus papillomas are rare intraventricular papillary neoplasms, typically in children and young adults.
Entity name
Non-Hodgkins lymphoma (NHL)
Note
An association of BCLAF1 single nucleotide polymorphisms (tagSNPs rs797558 and rs703193, P = 0.0097) with NHL was made following genotyping of 441 newly diagnosed NHL cases and 475 frequency-matched controls (Kelly et al., 2010).
Disease
Non-Hodgkins lymphoma refers to several subtypes of lymphoma that are distinct from Hodgkins lymphoma, such as Mantle cell lymphoma, diffuse large B cell lymphoma and follicular lymphoma (Sawas et al., 2011).
Entity name
Note
No changes in BCLAF1 were found in 43 samples of CMF (Romeo et al., 2010).
Disease
Chondromyxoid fibroma (CMF) is an uncommon benign cartilaginous tumor of bone usually occurring in adolescents (Ralph, 1962; Romeo et al., 2009). CMF is associated with recurrent rearrangements of chromosome bands 6p23-25, 6q12-15, and 6q23-27.

Bibliography

Pubmed IDLast YearTitleAuthors
78944801994Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy.Bione S et al
187941512008Regulation of cyclin D1 RNA stability by SNIP1.Bracken CP et al
164814762006Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation.Frock RL et al
150092152004Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy.Haraguchi T et al
192763702009TWIST-1 is overexpressed in neoplastic choroid plexus epithelial cells and promotes proliferation and invasion.Hasselblatt M et al
166411002006Quantitative phosphoproteomics of vasopressin-sensitive renal cells: regulation of aquaporin-2 phosphorylation at two sites.Hoffert JD et al
103301791999Btf, a novel death-promoting transcriptional repressor that interacts with Bcl-2-related proteins.Kasof GM et al
208555362010Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma.Kelly JL et al
214547092011The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation.Kong S et al
201237362010TRAP150 activates pre-mRNA splicing and promotes nuclear mRNA degradation.Lee KM et al
175704792007Systematic discovery of in vivo phosphorylation networks.Linding R et al
179382032007Protein kinase C delta induces transcription of the TP53 tumor suppressor gene by controlling death-promoting factor Btf in the apoptotic response to DNA damage.Liu H et al
126845332003MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans.Liu J et al
156818502005Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-to-autointegration factor.Mansharamani M et al
190089202009Essential role for Bclaf1 in lung development and immune system function.McPherson JP et al
170955402007Protein composition of human mRNPs spliced in vitro and differential requirements for mRNP protein recruitment.Merz C et al
96405321998The cellular organization of gene expression.Misteli T et al
140385861962Chondromyxoid fibroma of bone.RALPH LL et al
197059202009The proapoptotic C16-ceramide-dependent pathway requires the death-promoting factor Btf in colon adenocarcinoma cells.Rénert AF et al
206967772010Heterogeneous and complex rearrangements of chromosome arm 6q in chondromyxoid fibroma: delineation of breakpoints and analysis of candidate target genes.Romeo S et al
197009402009Benign cartilaginous tumors of bone: from morphology to somatic and germ-line genetics.Romeo S et al
151698732004Proteomic analysis of interchromatin granule clusters.Saitoh N et al
206615372010In search of a function for BCLAF1.Sarras H et al
216543862011New therapeutic targets and drugs in non-Hodgkin's lymphoma.Sawas A et al
115556362001Large-scale identification of mammalian proteins localized to nuclear sub-compartments.Sutherland HG et al
190989142009Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs.Ziegelbauer JM et al

Other Information

Locus ID:

NCBI: 9774
MIM: 612588
HGNC: 16863
Ensembl: ENSG00000029363

Variants:

dbSNP: 9774
ClinVar: 9774
TCGA: ENSG00000029363
COSMIC: BCLAF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000029363ENST00000353331Q9NYF8
ENSG00000029363ENST00000392348Q9NYF8
ENSG00000029363ENST00000527536E9PK91
ENSG00000029363ENST00000527613E9PKI6
ENSG00000029363ENST00000527759Q9NYF8
ENSG00000029363ENST00000529826E9PK09
ENSG00000029363ENST00000530429E9PQN2
ENSG00000029363ENST00000530767Q9NYF8
ENSG00000029363ENST00000531224Q9NYF8
ENSG00000029363ENST00000532384E9PKI6
ENSG00000029363ENST00000533422H0YF63
ENSG00000029363ENST00000533621H0YF00
ENSG00000029363ENST00000534269E9PJA7
ENSG00000029363ENST00000534762H0YF14
ENSG00000029363ENST00000628517E9PKI6
ENSG00000029363ENST00000640069A0A1W2PQ43

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
150092152004Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy.53
214547092011The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation.43
250910512014BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells.39
226453312012BclAF1 restriction factor is neutralized by proteasomal degradation and microRNA repression during human cytomegalovirus infection.36
179382032007Protein kinase C delta induces transcription of the TP53 tumor suppressor gene by controlling death-promoting factor Btf in the apoptotic response to DNA damage.33
206615372010In search of a function for BCLAF1.31
228330982012BCLAF1 is a radiation-induced H2AX-interacting partner involved in γH2AX-mediated regulation of apoptosis and DNA repair.26
282166612017miR-194-5p/BCLAF1 deregulation in AML tumorigenesis.21
197059202009The proapoptotic C16-ceramide-dependent pathway requires the death-promoting factor Btf in colon adenocarcinoma cells.18
208555362010Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma.18

Citation

John Peter McPherson

BCLAF1 (BCL2-associated transcription factor 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-06-01

Online version: http://atlasgeneticsoncology.org/gene/43164/bclaf1