MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

2014-09-01   Carolina Vicente-Dueñas , Ines González-Herrero , Idoia García-Ramírez , Isidro Sánchez-García 

Identity

HGNC
LOCATION
20q12
LOCUSID
ALIAS
DURS3,KRML,MCTO
FUSION GENES

Abstract

The MAFB protein is a basic leucine zipper (bZIP) transcription factor that plays important roles both in development and in the regulation of lineage-specific hematopoiesis. This gene contains no introns. The abnormal function of MAFB has been implicated in multiple myeloma, myeloid leukemias, multicentric carpotarsal osteolysis, Dupuytrens disease and nonsyndromic cleft lip.

DNA/RNA

Note

The MAFB open reading frame is encoded by a unique exon.

Description

MAFB gene maps to chromosome 20q11.2-q13.1, consists of a single exon and spans around 3 kb (Cordes and Barsh, 1994; Sieweke et al., 1996).

Transcription

1 exon, 3378 bp.
Ubiquitous expression of MAFB.

Proteins

Note

MAF family members, such as MAFB, are basic region/leucine zipper transcription factors that affect transcription positively or negatively, depending on their partner proteins and the context of the target promoter (Wang et al., 1999).
Atlas Image
Protein structure of MAFB.

Description

Sequence length: 323 aa.
Molecular mass of 35792 Da.
Sequence similarities: MAFB belongs to the bZIP family. MAF family contains one bZIP (basic-leucine zipper) domain.

Expression

MAFB is expressed in the digestive, endocrine and in immature myeloid/monocytic cells but not in lymphocytes.

Localisation

Intracellular, nucleus.

Function

Transcription factor; DNA binding protein.
MAFB acts as a transcriptional activator or repressor. It plays a role in erythroid differentiation and in the haematopoietic system it is expressed in immature myeloid/monocytic cells but not in lymphocytes (Kelly et al., 2000). MAFB plays a pivotal role in regulating lineage-specific hematopoiesis by repressing ETS1-mediated transcription of erythroid-specific genes in myeloid cells (Zanocco-Marani et al., 2009). It is also required for monocytic, macrophage, podocyte and islet beta cell differentiation (Kelly et al., 2000; Sevinsky et al., 2004; Bakri et al., 2005; Gemelli et al., 2008; Vanhoose et al., 2008; Aziz et al., 2009). SUMO modification controls its transcriptional activity and ability to specify macrophage fate (Tillmanns et al., 2007). Together with MAFA, MAFB regulates PDX1 transcription in pancreatic beta cells (Vanhoose et al., 2008). It is also involved in renal tubule survival and F4/80 maturation (Moriguchi et al., 2006). This protein activates the insulin and glucagon promoters. Together with PAX6, MAFB transactivates weakly the glucagon gene promoter through the G1 element (Gosmain et al., 2010). MAFB induces osteoclastogenesis and is essential for normal renal development (Zankl et al., 2012). It is a regulator of hindbrain segmentation and interacts with the ICD of LRP1 through a leucine zipper domain (Petersen et al., 2004). It is involved either as an oncogene or as a tumor suppressor, depending on the cell context, in multiple myeloma and myeloid leukemia development (Eychène et al., 2008).
It is implicated in the following physiological biological processes: rhombomere 6 development; segment specification; negative regulation of erythrocyte differentiation; inner ear morphogenesis; sensory organ development; transcription, DNA-dependent; thymus development; T cell differentiation in the thymus; positive regulation of transcription from RNA polymerase II promoter; respiratory gaseous exchange; rhombomere 5 development; brain segmentation.

Homology

MAFB shares 84% amino acid identity with its murine homolog.

Implicated in

Entity name
Disease
Multiple myeloma, also known as plasma cell myeloma, is a cancer of plasma cells. In multiple myeloma, collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells. Most cases of multiple myeloma also feature the production of a paraprotein - an abnormal antibody which can cause kidney problems. Bone lesions and hypercalcemia (high blood calcium levels) are also often encountered. MAFB is a specific marker for the prognostic unfavorable t(14;20)(q32;q12) in multiple myeloma patients (Stralen et al., 2009).
Prognosis
With high-dose therapy followed by autologous stem cell transplantation, the median survival has been estimated to be approximately 4.5 years in 2013, compared to a median of approximately 3.5 years with "standard" therapy (Child et al., 2003). Overall the 5-year survival rate is around 35% (Seiter et al., 2013).
Cytogenetics
Translocation t(14;20)(q32;q12).
Hybrid gene
IGH-MAFB given rise to and aberrant expression of MAFB.
Atlas Image
Translocation t(14;20) is implicated in multiple myeloma. Chromosomal translocations of the immunoglobulin heavy chain (IgH) gene region at 14q32 are regularly involved in B lymphoid malignancies. The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB.
Fusion protein
No fusion protein. Only aberrant expression of MAFB.
Oncogenesis
Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of MAF oncogenes (associated to human plasma cell neoplasias) are targeted to mouse B cells, the resulting animals fail to reproduce the human disease. An engineered transgenic mice that express MafB in haematopoietic stem/progenitor cells (HS/PCs) reproduced human multiple myeloma disease suggesting that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias (Vicente-Dueñas et al., 2012b). And the loss of p53 exacerbates this tumor stem cell reprogramming process (Vicente-Dueñas et al., 2012a).
Entity name
Myeloid leukemia
Note
MAFB gene is deleted in myeloid leukemias (Wang et al., 1999). A deletion of the long arm of chromosome 20 [del(20q)] is a recurring abnormality in a wide spectrum of myeloid disorders. Loss of genetic material from 20q seems to confer a proliferative advantage to myeloid cells, possibly through loss of function of a tumor suppressor gene (Wang et al., 1998).
Disease
Myeloid leukemia is a type of leukemia affecting myeloid tissue. There are two main types, acute myeloid leukemia and chronic myelogenous leukemia.
Cytogenetics
Deletion of the long arm of chromosome 20.
Entity name
Multicentric carpotarsal osteolysis (MCTO)
Note
Multicentric carpotarsal osteolysis is due to a heterozygosity missense mutations in the MAFB gene. The mutations were clustered within a 51-bp region of the single exon of MAFB at the N-terminal transcription activation domain. The allelic variants are: THR62PRO; SER70ALA; SER70LEU; PRO71SER; PRO71LEU and PRO54LEU (Zankl et al., 2012).
Disease
Defects in MAFB are the cause of multicentric carpotarsal osteolysis syndrome (MCTO). MCTO is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bone usually occurs and other bones may also be involved.
Chronic renal failure is a frequent component of the syndrome. Mental retardation and minor facial anomalies have been noted in some patients. The main clinical features are progressive destruction of the carpal and tarsal bone and other bones may also be involved, associated with chronic renal failure, mental retardation and minor facial anomalies.
Entity name
Dupuytrens disease (DD)
Note
Microarray analysis identified significantly upregulatation of MAFB among other genes in Dupuytrens disease. MAFB immunohistochemistry showed positive staining in 50% of the DD specimens studied (Lee et al., 2006).
Disease
Dupuytrens disease is characterized by fibroblastic proliferation of the palmar fascia, often leading to flexion contracture in the hand, where the fingers bend towards the palm and cannot be fully extended (Lee et al., 2006). Dupuytrens contracture progresses slowly and is often accompanied by some aching and itching. In patients with this condition, the palmar fascia thickens and shortens so that the tendons connected to the fingers cannot move freely. Incidence increases after the age of 40.
Entity name
Nonsyndromic cleft lip (NSCLP)
Note
Nonsyndromic cleft lip with or without cleft palate is a common isolated orofacial birth defect. The etiology of NSCLP is complex with both genetic and environmental factors implicated, but to date approximately only 20% of the genetic susceptibility has been identified (Vieira, 2008). Genome-wide association studies support for the association of MAFB and NSCLP (Yuan et al., 2011).
Disease
Cleft lip is a type of clefting congenital deformity caused by abnormal facial development during gestation. It is the non-fusion of the bodys natural structures that form before birth. A cleft lip or palate can be successfully treated with surgery, especially so if conducted soon after birth or in early childhood.

Bibliography

Pubmed IDLast YearTitleAuthors
198929882009MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages.Aziz A et al
155988172005Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate.Bakri Y et al
127362802003High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.Child JA et al
80011301994The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor.Cordes SP et al
191430532008A new MAFia in cancer.Eychène A et al
188327252008The vitamin D3/Hox-A10 pathway supports MafB function during the monocyte differentiation of human CD34+ hemopoietic progenitors.Gemelli C et al
205920232010Pax6 controls the expression of critical genes involved in pancreatic {alpha} cell differentiation and function.Gosmain Y et al
107903652000MafB is an inducer of monocytic differentiation.Kelly LM et al
164736812006Expression of a novel gene, MafB, in Dupuytren's disease.Lee LC et al
168473252006MafB is essential for renal development and F4/80 expression in macrophages.Moriguchi T et al
151350462004Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development.Petersen HH et al
151218702004Extracellular signal-regulated kinase induces the megakaryocyte GPIIb/CD41 gene through MafB/Kreisler.Sevinsky JR et al
86205361996MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation.Sieweke MH et al
188302542009MafB oncoprotein detected by immunohistochemistry as a highly sensitive and specific marker for the prognostic unfavorable t(14;20) (q32;q12) in multiple myeloma patients.Stralen E et al
175484682007SUMO modification regulates MafB-driven macrophage differentiation by enabling Myb-dependent transcriptional repression.Tillmanns S et al
185229392008MafA and MafB regulate Pdx1 transcription through the Area II control region in pancreatic beta cells.Vanhoose AM et al
229030612012A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors.Vicente-Dueñas C et al
182188362008Unraveling human cleft lip and palate research.Vieira AR et al
104443281999Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias.Wang PW et al
94913171998Refinement of the commonly deleted segment in myeloid leukemias with a del(20q).Wang PW et al
215679102011Association of ABCA4 and MAFB with non-syndromic cleft lip with or without cleft palate.Yuan Q et al
223870132012Multicentric carpotarsal osteolysis is caused by mutations clustering in the amino-terminal transcriptional activation domain of MAFB.Zankl A et al
193320552009TFE3 transcription factor regulates the expression of MAFB during macrophage differentiation.Zanocco-Marani T et al

Other Information

Locus ID:

NCBI: 9935
MIM: 608968
HGNC: 6408
Ensembl: ENSG00000204103

Variants:

dbSNP: 9935
ClinVar: 9935
TCGA: ENSG00000204103
COSMIC: MAFB

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000204103ENST00000373313Q9Y5Q3

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Developmental BiologyREACTOMER-HSA-1266738
Activation of HOX genes during differentiationREACTOMER-HSA-5619507
Activation of anterior HOX genes in hindbrain development during early embryogenesisREACTOMER-HSA-5617472

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713366Tumor necrosis factor alpha (TNF-alpha) inhibitorsChemicalClinicalAnnotationassociatedPD
PA283MAPK8GenePathwayassociated23922006
PA30621MAPK14GenePathwayassociated23922006
PA443434Arthritis, RheumatoidDiseaseClinicalAnnotationassociatedPD

References

Pubmed IDYearTitleCitations
190609062009Common variants at 30 loci contribute to polygenic dyslipidemia.552
204364692010A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4.200
204364692010A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4.200
238636252013Inactivation of specific β cell transcription factors in type 2 diabetes.162
186151562008Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis.68
232251512013miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B.58
155988172005Balance of MafB and PU.1 specifies alternative macrophage or dendritic cell fate.46
243275622013A Gata3-Mafb transcriptional network directs post-synaptic differentiation in synapses specialized for hearing.32
229030612012A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors.28
205818302010The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3.25

Citation

Carolina Vicente-Dueñas ; Ines González-Herrero ; Idoia García-Ramírez ; Isidro Sánchez-García

MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

Atlas Genet Cytogenet Oncol Haematol. 2014-09-01

Online version: http://atlasgeneticsoncology.org/gene/41236/mafb-(v-maf-avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-b)