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ZBTB7A (zinc finger and BTB domain containing 7A)

Written2011-07Kalliopi Apostolopoulou, Ioannis S Pateras, Athanassios Kotsinas, Vassilis G Gorgoulis
University of Athens, Faculty of Medicine, Department of Histology, Embryology, Molecular Carcinogenesis Group, Athens, Greece

(Note : for Links provided by Atlas : click)

Identity

Alias_namesZBTB7
zinc finger and BTB domain containing 7
Alias_symbol (synonym)FBI-1
LRF
DKFZp547O146
pokemon
ZNF857A
Other aliasFBI1
MGC99631
HGNC (Hugo) ZBTB7A
LocusID (NCBI) 51341
Atlas_Id 42863
Location 19p13.3  [Link to chromosome band 19p13]
Location_base_pair Starts at 4043304 and ends at 4065529 bp from pter ( according to hg19-Feb_2009)  [Mapping ZBTB7A.png]
Local_order - EEF2 (19pter-q12) eukaryotic translation elongation factor 2
- SNORD37 (19p13.3) small nucleolar RNA, C/D box 37
- PIAS4 (19p13.3) protein inhibitor of activated STAT, 4
- ZBTB7A (19p13.3) zinc finger and BTB domain containing 7A
- MAP2K2 (19q13.3) mitogen-activated protein kinase kinase 2
- CREB3L3 (19p13.3) cAMP responsive element binding protein 3-like 3
Fusion genes
(updated 2016)
TGFBR2 (3p24.1) / ZBTB7A (19p13.3)ZBTB7A (19p13.3) / DKK2 (4q25)ZBTB7A (19p13.3) / TNK1 (17p13.1)

DNA/RNA

 
  Schematic diagram depicting the structure and 19p13.3 chromosomal localization of the ZBTB7A/POKEMON gene.
Description Size: 21601 bases.
Orientation: minus strand.
Cloning of the 5'-upstream region of ZBTB7A revealed: a) the absence of putative TATA and CCAAT sequences, b) the presence of two consensus sequences for the binding transcription factor Sp1, SpA (-641~636-) and SpB (-972~-967), as well as consensus sequences for the AP-1, AP-2, PU.1, Hb, CBF-1, GATA-1 elements and p53-binding sites, c) the presence of three regulatory elements, POS-D, NEG-U and NEG-D, with a key role in the regulation of the Pokemon gene.
The nucleotide sequence from -83 to -71 contains the positive element POS-D, which is necessary for the strong activity of the Pokemon promoter. The region from -558 to -541 contains the NEG-U element, involved in the negative regulation of the Pokemon promoter. The region from -128 to -108, namely NEG-D, is also necessary for the negative regulation of the Pokemon promoter. Neither NEG-U nor NEG-D element alone can negatively affect Pokemon expression. Pokemon promoter activity is greatly dependent on the interaction (cooperation) between NEG-U and NEG-D elements. This synergistic inhibition on Pokemon expression requires a specific length between the regulatory elements. Once this distance is reduced, the interaction between the NEG-U and NEG-D elements is almost abolished.
Transcription The gene is comprised of 3 exons, building a main transcript of 4456 bps.

Alternative splicing
Pokemon transcripts can be alternatively spliced, resulting in four mRNAs with different 5'-untranslated regions. The four alternative first exons are located at -11596, -10224, -9109 and -17 bp upstream of the translation start site of Pokemon, implying that Pokemon can putatively be regulated by four alternative promoters.

Pseudogene There are no known pseudogenes.

Protein

 
  Schematic representation of human ZBTB7A protein structure. POZ domain: 24-131, ZF: 376-489, NLS: 489-503.
Description ZBTB7A protein is composed of 584 amino acids (a.a.) with a molecular weight of 86 kDa. It belongs to the POK (POZ and Krüppel) family of transcriptional repressors. Members of this family have a characteristic structure, containing a NH2-terminal POZ/BTB domain (poxvirus zinc finger/broad-complex tramtrack, bric-à-brac) and a COOH-terminal domain, consisting of C2H2 Krüppel-type zinc fingers, "surnamed" due to resemblance with the Drosophila segmentation protein Krüppel. Due to this structure, they are also known as POZ/ZF proteins. At the C-terminus a bipartite nuclear localization signal (NLS) is located.
POZ/BTB domain represents a 120 a.a. evolutionary conserved domain, present in more than 200 human proteins, which mediates protein-protein interactions. It is responsible for homodimerization as well as heterodimerization mediating the recruitment of corepressor complexes, such as nuclear co-repressor (N-CoR), silencing mediator of retinoic acid (SMRT), B-CoR (Bcl-6 co-repressor), mSin3A (SIN3 homolog A, transcription regulator) to the target genes. This also facilitates the binding of histone deacetylases within the target genes leading to its transcriptional repression. It also interacts with Sp1 zinc finger proteins.
C2H2 Krüppel-type zinc finger domain, found in more than 600 human proteins, represents a 25-30 a.a. domain, responsible for specific DNA recognition and binding. It is characterised by two conserved cysteine and histidine residue pairs that coordinate a single zinc atom.
Expression ZBTB7A is expressed in all proliferating cells. ZBTB7A is highly expressed in malignant tissues than in the corresponding benign or normal tissue (breast, lung, prostate).
Localisation ZBTB7A is constitutively nuclear, due to a Nuclear Localization Signal (NLS) located at the C-terminus (a.a. 498-502). Immunohistochemical (IHC) studies of ZBTB7A expression in NSCLCs (Non-small cell lung carcinomas) have shown a nuclear signal. In NSCLCs the immunostaining is prevalent in the cancerous nests, whereas few tumour-associated stromal cells and a small number of parabasal intermediate cells in the adjacent normal bronchial epithelium, are positively stained. ZBTB7A nuclear expression was also prevalent in malignant breast tissues and surrounding fibroblasts and lymphocytes, whereas stromal cells were weakly stained.
Function ZBTB7A has a variety of biological functions. ZBTB7A was originally identified as a factor binding to a specific sequence within the human immunodeficiency virus, type 1 promoter, and can physically interact with other POK family members such as BCL-6. Co-expression of ZBTB7A and BCL-6 in lymphoma, predicts the clinical outcome. ZBTB7A is also implicated in differentiation processes like osteoclastogenesis, chondrogenesis and adipogenesis. Furthermore, ZBTB7A knockdown in mice, results in embryonic lethality due to severe anaemia and impaired cellular differentiation.
ZBTB7A is a transcription factor which regulates the expression of many proteins, such as extracellular matrix collagen types I, II, IX, X and XI, fibronectin, elastin, human cartilage oligomeric matrix protein, p19ARF tumour suppressor and the c-fos and c-myc oncoproteins by binding to consensus sequence within their promoters. ZBTB7A preferable binding sites include either a single guanine-rich site or two half-sites, each with the consensus sequence G(A/G)GGG(T/C)(C/T)(T/C)(C/T), with a variety in spacing and orientation, supporting that ZBTB7A can bind to the DNA with great flexibility. In other cases, the interaction between Pokemon POZ domain and other transcription factors, such as Sp-1 or the p65 subunit of NF-kappaB, is necessary for its regulatory role.
ZBTB7A self-associates, as depicted in vivo and in vitro, via both its POZ domain and its zinc finger (ZF) domain. ZBTB7A can act as a transcriptional repressor or activator depending on the promoter context.
Finally, it plays a crucial role in cell tumorigenesis.

- Transcription regulator

1. ZBTB7A/FBI-1 + IST (HIV)
FBI-1 binds to IST, the HIV-1 inducer of short transcripts, and mediates its function. The first and second zinc fingers are required for efficient binding. FBI-1, via the zinc finger domain, interacts as well with Tat (transactivator of transcription), a viral transactivator protein, responsible for the synthesis of HIV-1 full-length transcripts. FBI-1 partially colocalizes with Tat and enhances its activity in a dose dependent manner, therefore modulating Tat-activated HIV-1 transcription.

2. FBI-1 + adipogenesis
FBI-1 acts as a dual regulator in adipogenesis. It promotes preadipocyte differentiation process and facilitates adipogenesis. On the other hand, it is implicated in termination of the mitotic clonal expansion, in which growth-arrested preadipocytes re-enter the cell cycle and complete two rounds of cell division, followed by terminal differentiation phase.

3. FBI-1 + FASN (transcriptional activator)
Increased FBI-1 expression enhances FASN (fatty-acid synthase gene) expression, in stable cancer cells or immortalised stable cells. FASN expression appears to be low in almost all nonmalignant adult tissues, but is highly expressed in many carcinomas, where it is responsible for fatty acid synthesis. Furthermore, knockdown of FBI-1 expression leads to decreased FASN expression.
FBI-1 enhances FASN transcriptional activation through SREBP-1a (sterol-responsive element (SRE)-binding protein 1). FBI-1 and SREBP-1a form a complex and co-localize mainly in the nucleus. Specifically, FBI-1 through its ZFDBD-C-term domain (zinc finger DNA binding domain) interacts directly with the bHLH domain of SREBP-1. Sp1 binds to the proximal GC-box of the FASN promoter and acts as a major activator. It has been found that the regulatory elements GC-box and SRE/E-box of FASN promoter can be bound by all three, FBI-1, SREBP-1a and Sp1, transcription factors. This can lead to a binding competition between them.

4. FBI-1 + NF-kappaB (transcriptional activator)
FBI-1 POZ domain interacts directly with the RHD domain (Rel homology domain) of NF-kappaB p65 subunit.
FBI-1 enhances the transcription of NF-kappaB-responsive genes, like E-selectin, by increasing either the localization or stability of NF-kappaB in the nucleus. FBI-1 facilitates nuclear import and prolonged nuclear retention of the p65 subunit of NF-kappaB, either by inhibiting its export to the cytoplasm, or by increasing its stability. In addition, FBI-1 inhibits IkappaB (inhibitors of NF-kappaB) interaction with NF-kappaB, eventually enhancing NF-kappaB transcription in the nucleus.

5. FBI-1 + ADH5/FDH (transcriptional repressor)
FBI-1 POZ domain interacts with the C2H2-type zinc-finger domain of Sp1 (Specificity protein 1), thereby repressing the ADH5/FDH promoter activity.

6. ZBTB7A + ARF (transcriptional repressor)
ZBTB7A was characterized as a potential proto-oncogene that specifically represses transcription of p14ARF, a major tumour suppressor gene, (leading indirectly to p53 inactivation). ZBTB7A binds directly to p19ARF promoter (mouse homologue). ARF promoter contains several putative ZBTB7A-binding sites, rich in GC. However the one located 50 base pairs upstream from the transcription start site is indispensable for p19ARF repression.

7. FBI-1 + p21WAF1/CIP1 (transcriptional repressor)
FBI-1 represses transcriptional activation of P21CIP1, by the following ways.
Firstly, by inhibiting ARF and Hdm2 expression, and therefore p53, it indirectly affects p21WAF1/CIP1 expression. Secondly, as a GC-box-binding transcription factor, it competes with Sp1 (transcriptional activator) to bind to the GC-rich FRE/GC-box 3 element at the proximal promoter, critical for p21CIP1 transcription.
Furthermore FBI-1 competes with p53 for binding to the distal p53-binding elements of p21WAF1/CIP1 and represses its transcription.
Additionally, it interacts with corepressors such as NCoR (Nuclear receptor co-repressor), SMRT (silencing mediator for retinoid and thyroid receptors), and mSin3A and recruits HDAC complexes, leading to histone deacetylation at the proximal promoter, responsible for p21WAF1/CIP1 transcriptional repression.

8. FBI-1 + CCS-3 + p21WAF1/CIP1
FBI-1 suppresses p21WAF1/CIP1 promoter activation by more than 70% by acting on both the proximal Sp1 binding GC-box 3 element and the distal p53 responsive regulatory elements. CCS-3, (cervical cancer suppressor -3), represents an isoform of eEF1A (eukaryotic translation elongation factor 1A), involved in various processes like embryogenesis, oncogenic transformation, senescence, cell proliferation, and cytoskeletal organization. CCS-3 enhances the FBI-1 mediated p21WAF1/CIP1-transcriptional repression, by another 30-50%. The above is accomplished because CCS-3 can interact with both co-repressors, (like SMRT and NCoR independently of FBI-1) and FBI-1 POZ domain. CCS-3 is able to recruit additional transcriptional co-repressor-HDAC complexes when bound to the FBI-1 POZ-domain, therefore enhancing FBI-1 transcriptional repression potential.
Furthermore, both FBI-1 and CCS-3 independently promote cell proliferation. Co-transfection of CCS-3 and FBI-1 results in a significant increase in cell population.

9. LRF - COMP (transcriptional repressor)
LRF (mouse homolog of FBI-1) binds directly to the NRE element and specifically to a nine nucleotide (GAGGGTCCC) sequence - LRF binding element (LBE) in COMP (Cartilage oligomeric matrix protein) gene promoter. NRE represents a negative regulatory element, both necessary and sufficient to repress promoter activity. Therefore, it regulates COMP gene expression implicated in chondrogenic differentiation. Human COMP gene promoter also contains a typical consensus site (GGGGGCCTC, -1294 to -1302) for binding LRF/FBI-1, implying that FBI-1 may suppress COMP gene expression in human as LRF does in the mouse.

10. FBI1 - AR (transcriptional repressor)
The androgen receptor (AR) is important for the proliferation and functioning of prostate cells.
FBI-1 physically interacts with AR and when overexpressed, it represses AR transcriptional activity in a ligand-dependent manner. More precisely, POZ domain of FBI1 is responsible for the interaction with the LBD domain (C-terminal ligand-binding domain) of AR. Furthermore, full-length FBI-1 is indispensable for the repression of AR transcriptional activity. On the contrary, FBI-1 suppression by siRNA enhanced AR transcriptional activity.
It is known that FBI-1 can interact with NCoR and SMRT, which are co-repressors of AR. (FBI-1 exhibited a much stronger interaction with SMTR compared to that with NCoR). It was shown that FBI-1 enhances the recruitment of NCoR and SMRT to endogenous ARE elements and through this mechanism it suppresses AR transcriptional activity. This notion is further supported by the fact that FBI-1 repressive effect on AR transcriptional activity, is inhibited upon endogenous NCoR and SMRT knockdown. Furthermore it was suggested that FBI-1 could recruit a co-repressor complex harbouring HDACs, resulting in repression of AR functions in the presence of R1881 (synthetic agonist of the androgen receptor). Last, it was shown that FBI-1 can play different roles in regulating androgen-dependent (LNCaP) and -independent (PC-3) prostate cancer cells. It inhibits LNCaP cell proliferation in the presence of R1881, whereas no difference in proliferation was observed in the absence of R1881. In contrast, knockdown of FBI-1 by siRNA led to a significant increase in LNCaP cell growth. Interestingly, either in the presence or absence of R1881, PC-3 cell proliferation was dramatically enhanced upon FBI-1 overexpression.

11. Pokemon - survivin (transcriptional activator)
Tissue microarray technology has shown Pokemon overexpression in 86,8% of breast cancer tissue, but not in normal breast tissue. Furthermore Pokemon expression correlated positively with tumor size, lymph node metastasis and poor patient survival.
Survivin, a member of the inhibitor of apoptosis proteins (IAP), is implicated in cell carcinogenesis and tumor progression.
Survivin and Pokemon expression levels were found to be highly correlated in human breast cancer cells. Pokemon induces survivin expression by direct binding to the GC boxes in its promoter.

- Relation with ASF/SF2 through miRNAs

LRF is regulated by microRNA (miRNA) families.
In MEFs (Mouse Embryo Fibroblasts) it was shown that miR-28 and miR-505, which are negatively controlled by LRF, can affect ASF/SF2 (Alternative Splicing Factor/Splicing Factor 2) expression and therefore can induce apoptosis or cellular transformation. Deregulation of the LRF/miR-28/miR-505/ASF/SF2 axis affects the MEF senescence/apoptosis pathway.

- Relation with anticancer agents

Curcumin is a natural compound known for its antioxidant, anti-inflammatory and anticarcinogenic properties, since it can inhibit the proliferation and induce the apoptosis of cancer cells, such as gastric, colon, breast. Curcumin inhibits ZBTB7A transcriptional activation, by suppressing the Sp1 stimulatory effect on Pokemon promoter, as it inhibits Sp1 recruitment to the Pokemon promoter.

- Global mapping of ZBTB7A downstream target genes in HepG2 cells

ChIP-on-chip analysis performed in the human hepato-carcinoma cancer cell line HepG2, revealed 556 genes as potential direct targets of ZBTB7A. These genes are mainly divided in three categories: genes regulating metabolism, transcriptional regulators and cell signal transduction genes. Among the most ZBTB7A-targeted metabolic pathways are the aminosugar, arachidonic acid, tryptophan, pyrimidine and purine metabolic pathways. Moreover sucrose, vitamin B6, valine, leucine and isoleucine, folate, fatty acid and glycerolipid metabolism, are characterized as ZBTB7A regulatory targets. As far as signal transduction is concerned, ZBTB7A might play a regulatory role on the MAPK signalling pathway. Furthermore, four genes involved in axon guidance, a key stage in the formation of the neuronal network, are directly regulated by ZBTB7A expression in HepG2 cells. This pinpoints to a potential regulatory role for ZBTB7A in neural development.

- ZBTB7A and SUMOylation

ZBTB7A can be sumoylated as it contains an amino-acid sequence highly similar to the SUMO-1 conjugate consensus motif, ψKXE (ψ: large hydrophobic residue, K: lysine to which SUMO-1 is conjugated, X: any amino acid, and E: glutamic acid). Sumoylation of several lysine residues of ZBTB7A is important in order to achieve full repressive activity.

Homology LRF (leukemia/lymphoma-related factor) is the mouse homologue of FBI-1. It co-immunoprecipitates and co-localizes with Bcl-6 and is involved in chondrogenesis and adipogenesis.
OCZF (osteoclast-derived zinc finger), the rat homologue of FBI-1, is a transcription repressor, involved in osteoclastogenesis. Mouse LRF and rat OCZF are 90 and 96% identical at the nucleotide and amino acid levels, respectively. Mouse LRF and human FBI-1 sequences are 89% identical at the amino acid level.

Mutations

Note No known mutations.

Implicated in

Note
  
Entity Carcinogenesis
Note Since ZBTB7A specifically represses transcription of p14ARF, a major tumor suppressor gene, it was characterized as a potential proto-oncogene, expected to play a significant role in carcinogenesis. ZBTB7A null MEFs (ZBTB7A-/-) had higher p19ARF protein levels than wild-type MEFs and resisted to proliferation and transformation upon oncogenic stimulation. The oncogenic nature of ZBTB7A was also examined in vivo in transgenic mice, which overexpressed ZBTB7A in T and B lymphoid lineage cells. These mice developed thymic lymphomas and tumour infiltration into bone marrow and poor survival compared to the wild-type ones.
ZBTB7A is overexpressed in diffuse large B cell lymphomas (DLBCL) and follicular lymphomas, as well as in anaplastic large cell lymphoma and angioimmunoblastic lymphoma, as far as T-cell malignancies are concerned.
ZBTB7A oncogenic role in human malignant gliomas was revealed with comparative genomic hybridization analysis (bioinformatics methods).
Tissue microarray analysis revealed ZBTB7A overexpression in colon, prostate, bladder, as well as in breast and lung carcinomas.
IHC and immunofluorescence analysis revealed a significantly higher expression of LRF protein in malignant breast specimens than in the corresponding benign or normal tissue, with a clear nuclear expression pattern. 40% and 15% of benign breast biopsy tissues expressed LRF mRNA transcripts and protein, respectively, probably because they contain premalignant cells and adipocytes.
Ductal hyperplasia showed weak LRF staining, whereas in invasive ductal carcinoma and invasive lobular carcinoma strong nuclear expression of LRF was observed.
In breast cancer tissues ZBTB7A expression levels were significantly correlated with histological grade, implying a potential role of ZBTB7A in breast cancer development, whereas were inversely correlated with the oestrogen receptor status. No correlation was confirmed between ZBTB7 overexpression and tumour size, stage, lymph node status, or PR status. However its overexpression predicted poorer overall survival and was associated with shorter recurrence-free survival. In addition, ZBTB7A is expressed in the nuclei of human colon, renal, hepatocellular carcinomas, mesotheliomas and thymoma tumor cells.
IHC and immunoblotting analysis showed ZBTB7A overexpression in NSCLC specimens, compared to adjacent normal tissue elements. Gene amplification proved to be a relatively frequent event leading to ZBTB7A overproduction in NSCLCs. Furthermore, a positive correlation between ZBTB7A expression and proliferation, as well as tumour size, was revealed. Survival analysis correlated ZBTB7A overexpression with poor prognosis. ZBTB7A expression is not associated with the NSCLC patients' sex, age, lymph node stage, tumor differentiation degree and histology.
Furthermore IHC, immunoblotting and PCR analysis revealed significantly higher ZBTB7A (FBI-1) protein and mRNA expression levels in ovarian cancer samples and cell lines, compared to benign or borderline tumours. Gene amplification was proved to be, to a great proportion, the underlying mechanism of ZBTB7A overexpression in ovarian cancers. Upregulated ZBTB7A expression was found in metastatic foci and malignant ascites and was associated with advanced stage, poor overall survival and disease-free survival. Additionally, it was shown that ZBTB7A plays an important role in ovarian cancer cell migration, proliferation and invasiveness, through its direct binding to the promoter of MT1-MMP (membrane type 1-matrix metalloproteinase), which enhances MT1-MMP promoter activity.
Moreover, ZBTB7A (LRF) is implicated in the pathogenesis of prostate cancer, since IHC, Western blot and PCR analyses revealed a significantly higher expression of LRF mRNA transcripts and protein in prostate cancer (PC) specimens than in benign prostate hyperplasia (BPH). A significant increase in LRF mRNA transcripts and protein levels was observed when normal human prostate cells (RWPE-1) as well as prostate cancer cells, (LNCaP androgen sensitive prostate cancer cells and PC-3 androgen-insensitive prostate cancer cells), were treated with EGF (epidermal growth factor).
Recently, the development of a novel strategy for silencing Pokemon in vivo, with promising results, provided a marked anti-tumour activity in nude mice.
  
  
Entity Cell growth and proliferation
Note ZBTB7A is implicated in cell growth regulation, as it transcriptionaly represses Rb (Retinoblastoma), a gene involved in differentiation, cell cycle control, and tumor suppression. FBI-1, through its POZ domain, recruits HDACs to deacetylate histones H3 and H4 around the Rb proximal promoter region, resulting in Rb transcriptional repression. Additionally, FBI-1 binds to the 4 FREs (FBI-1 binding sites, GC-rich) on the Rb promoter and relatively strongly to the FRE2 element.
FBI-1 enhances cellular transformation as well. FBI-1 overexpression in HeLa cells resulted in formation of large foci and increased the number of HeLa cells in S phase. Moreover ZBTB7A is involved in cell proliferation in MEFs.
  
  
Entity Differentiation
Note ZBTB7A is implicated in many differentiation processes including osteoclastogenesis, chondrogenesis and adipogenesis. ZBTB7A knockdown in mice resulted in embryonic lethality due to severe anaemia and impaired cellular differentiation. LRF was found to be essential for terminal fetal erythropoiesis. LRF is a downstream target of GATA1. GATA1 is a transcription factor significant for erythroblasts differentiation, maturation and protection from apoptosis. GATA1 binds directly to the two putative GATA-binding sites in ZBTB7A promoter region and activates its expression. Additionally, in the absence of LRF, both in embryos and adults, BIM a significant apoptosis inducer in hematopoietic cells was markedly upregulated. LRF directly binds to BIM proximal promoter region, which contains four potential LRF binding sites and represses its expression, during the late stages of erythroid differentiation. On the other hand, BIM loss rescues LRF knockout mice from fetal anemia.
From the above, it is resumed that the suppression of BIM-mediated apoptosis by LRF, which in turn is activated by GATA-1, is critical for effective erythropoiesis.

RANK and its ligand, RANKL (a member of the tumor necrosis factor - TNF superfamily), are critical molecules in osteoclastogenesis. RANKL also plays an important role in inflammatory bone loss. FBI-1/OCZF/LRF is highly expressed in osteoclasts and is an important regulator of RANKL-induced osteoclastogenesis. LRF siRNA inhibits osteoclast differentiation. Osteoclast formation is a crucial step in bone destruction in chronic arthritis. FBI-1/OCZF is highly expressed in osteoclasts in inflammatory arthritis, implying a role in inflammatory bone erosion. The above suggest that by enhancing osteoclastogenesis and survival of osteoclasts, FBI-1/OCZF/LRF might play important roles in bone destruction in vivo, including the bone loss and remodelling that occurs in chronic inflammatory arthropathies, such as rheumatoid arthritis.

  
  
Entity Regulation of B lymphopoiesis
Note LRF (mouse homologue of ZBTB7A) regulates B lymphocytes development from lymphoid-restricted progenitors in mice, versus T lymphoid fate. Knockdown of LRF in HSCs (hematopoietic stem cells) and CLPs (common lymphoid progenitors), impaired B cell development and resulted in extrathymic T cell development in the bone marrow (BM). Furthermore, LRF blocks Notch signalling pathway in normal HSCs. This pathway is essential for T cell development. Notch deletion in mouse HSCs results in a decreased number of thymic T cells, whereas it enhances B cell development in the thymus.
Moreover, LRF regulates mature B cell lineage fate and humoral immune responses, through the obligatory formation of a dimer in B cells, important for its function. Furthermore, LRF inactivation in transformed B cells attenuated their growth rate. The above suggest the potential targeting of LRF dimmers as a treatment of autoimmune diseases and B cell malignancies.
  
  
Entity LRF bypasses RASV12-induced senescence
Note LRF enhances E2F-dependent transcription, with an unknown mechanism, which does not include Rb downregulation. LRF synergizes with RASV12 in inducing E2F. LRF bypasses RASV12-induced senescence by activating E2F-target genes, such as Cyclin E, Cyclin A and p107. Specifically, Cyclin E is shown to be indispensable, but not sufficient for LRF-mediated bypass of RASV12-induced senescence. The above mentioned bypass occurs independently of critical senescence inducers, such as p19ARF, p21CIP and p16INK4A.
  
  
Entity LRF is post-transcriptionally controlled by MiR-20a: implications in senescence
Note MicroRNAs (miRNAs) are short 20-22 nucleotide RNA molecules, which act as post-transcriptional suppressors. They repress mRNA translation by base pairing to 3'UTR sequences.
Mir-20a, a member of miR-17-92 cluster, can interact directly with ZBTB7A 3'UTR. Upon miR-20a overexpression in MEFs, LRF protein is reduced by 40%. Conversely, miR-20a depletion resulted in increased LRF protein levels by 55%.
MiR-20a induces p19ARF expression to a smaller extent than siLRF. However, miR-20a is a more efficient senescence inducer than siLRF, implying the contribution of other factors to the senescence effect.
It has been shown that E2F1 expression is also under the miR-20a control in MEFs. When miR-20a is highly expressed there is a decrease in E2F1 protein levels, to a greater degree than that after siLRF. Conversely, miR-20a depletion slightly enhances E2F1 expression. However, E2F1 silencing by siE2F1 in MEFs is not enough to induce senescence, whereas miR-20a overexpression in LRF-null MEF, with the concomitant E2F1 downregulation, significantly enhances senescence. In addition, miR-20a and not siLRF, can also increase p16INK4A protein levels, a key player in senescence pathway, both in wild type and LRF-null MEFs.
The above data support the notion that miR-20a elicited cellular senescence results mainly from LRF downregulation and consequent p19ARF upregulation, with the contribution of E2F1 down-regulation and p16INK4A induction.
  
  
Entity P-glycoprotein (Pgp) and transcriptional repression of Pokemon
Note Pgp is a 170 kD protein, encoded by the human MDR1 (ABCB1) gene and belongs to the ATP-binding cassette transporters family. Pgp and the other family members function as pumps to extrude anticancer drugs from cancer cells and are related to drug resistance phenotype. Pgp is often over-expressed in drug-resistant cancer cells. It has been found that Pgp represses the transcription of Pokemon, through decreasing Pokemon promoter activity. Furthermore, this Pgp regulated suppression of Pokemon is p53 dependent.
  

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PMID 18801742
 
Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers.
Jiang L, Siu MK, Wong OG, Tam KF, Lam EW, Ngan HY, Le XF, Wong ES, Chan HY, Cheung AN.
Mol Cancer. 2010 Dec 21;9:318.
PMID 21176152
 
POZ for effect--POZ-ZF transcription factors in cancer and development.
Kelly KF, Daniel JM.
Trends Cell Biol. 2006 Nov;16(11):578-87. Epub 2006 Sep 22. (REVIEW)
PMID 16996269
 
The transcription factor FBI-1/OCZF/LRF is expressed in osteoclasts and regulates RANKL-induced osteoclast formation in vitro and in vivo.
Kukita A, Kukita T, Nagata K, Teramachi J, Li YJ, Yoshida H, Miyamoto H, Gay S, Pessler F, Shobuike T.
Arthritis Rheum. 2011 Sep;63(9):2744-54. doi: 10.1002/art.30455.
PMID 21590684
 
Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4.
Laudes M, Bilkovski R, Oberhauser F, Droste A, Gomolka M, Leeser U, Udelhoven M, Krone W.
J Mol Med (Berl). 2008 May;86(5):597-608. Epub 2008 Mar 27.
PMID 18368381
 
Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis.
Laudes M, Christodoulides C, Sewter C, Rochford JJ, Considine RV, Sethi JK, Vidal-Puig A, O'Rahilly S.
J Biol Chem. 2004 Mar 19;279(12):11711-8. Epub 2003 Dec 30.
PMID 14701838
 
FBI-1 enhances transcription of the nuclear factor-kappaB (NF-kappaB)-responsive E-selectin gene by nuclear localization of the p65 subunit of NF-kappaB.
Lee DK, Kang JE, Park HJ, Kim MH, Yim TH, Kim JM, Heo MK, Kim KY, Kwon HJ, Hur MW.
J Biol Chem. 2005 Jul 29;280(30):27783-91. Epub 2005 May 24.
PMID 15917220
 
POZ domain transcription factor, FBI-1, represses transcription of ADH5/FDH by interacting with the zinc finger and interfering with DNA binding activity of Sp1.
Lee DK, Suh D, Edenberg HJ, Hur MW.
J Biol Chem. 2002 Jul 26;277(30):26761-8. Epub 2002 May 9.
PMID 12004059
 
Leukemia/lymphoma-related factor, a POZ domain-containing transcriptional repressor, interacts with histone deacetylase-1 and inhibits cartilage oligomeric matrix protein gene expression and chondrogenesis.
Liu CJ, Prazak L, Fajardo M, Yu S, Tyagi N, Di Cesare PE.
J Biol Chem. 2004 Nov 5;279(45):47081-91. Epub 2004 Aug 26.
PMID 15337766
 
The transcription factor Pokemon: a new key player in cancer pathogenesis.
Maeda T, Hobbs RM, Pandolfi PP.
Cancer Res. 2005b Oct 1;65(19):8575-8. (REVIEW)
PMID 16204018
 
LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.
Maeda T, Ito K, Merghoub T, Poliseno L, Hobbs RM, Wang G, Dong L, Maeda M, Dore LC, Zelent A, Luzzatto L, Teruya-Feldstein J, Weiss MJ, Pandolfi PP.
Dev Cell. 2009 Oct;17(4):527-40.
PMID 19853566
 
Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF.
Maeda T, Merghoub T, Hobbs RM, Dong L, Maeda M, Zakrzewski J, van den Brink MR, Zelent A, Shigematsu H, Akashi K, Teruya-Feldstein J, Cattoretti G, Pandolfi PP.
Science. 2007 May 11;316(5826):860-6.
PMID 17495164
 
Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors.
Melnick A, Carlile G, Ahmad KF, Kiang CL, Corcoran C, Bardwell V, Prive GG, Licht JD.
Mol Cell Biol. 2002 Mar;22(6):1804-18.
PMID 11865059
 
FBI-1, a factor that binds to the HIV-1 inducer of short transcripts (IST), is a POZ domain protein.
Morrison DJ, Pendergrast PS, Stavropoulos P, Colmenares SU, Kobayashi R, Hernandez N.
Nucleic Acids Res. 1999 Mar 1;27(5):1251-62.
PMID 9973611
 
FBI-1 can stimulate HIV-1 Tat activity and is targeted to a novel subnuclear domain that includes the Tat-P-TEFb-containing nuclear speckles.
Pendergrast PS, Wang C, Hernandez N, Huang S.
Mol Biol Cell. 2002 Mar;13(3):915-29.
PMID 11907272
 
Flexible DNA binding of the BTB/POZ-domain protein FBI-1.
Pessler F, Hernandez N.
J Biol Chem. 2003 Aug 1;278(31):29327-35. Epub 2003 May 15.
PMID 12750370
 
Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts.
Pessler F, Pendergrast PS, Hernandez N.
Mol Cell Biol. 1997 Jul;17(7):3786-98.
PMID 9199312
 
The proto-oncogene LRF is under post-transcriptional control of MiR-20a: implications for senescence.
Poliseno L, Pitto L, Simili M, Mariani L, Riccardi L, Ciucci A, Rizzo M, Evangelista M, Mercatanti A, Pandolfi PP, Rainaldi G.
PLoS One. 2008 Jul 2;3(7):e2542.
PMID 18596985
 
ZBTB7 overexpression contributes to malignancy in breast cancer.
Qu H, Qu D, Chen F, Zhang Z, Liu B, Liu H.
Cancer Invest. 2010 Jul;28(6):672-8.
PMID 20394500
 
Regulation of pokemon 1 activity by sumoylation.
Roh HE, Lee MN, Jeon BN, Choi WI, Kim YJ, Yu MY, Hur MW.
Cell Physiol Biochem. 2007;20(1-4):167-80.
PMID 17595526
 
Pokemon expression in malignant glioma: an application of bioinformatics methods.
Rovin RA, Winn R.
Neurosurg Focus. 2005 Oct 15;19(4):E8.
PMID 16241110
 
The LRF transcription factor regulates mature B cell development and the germinal center response in mice.
Sakurai N, Maeda M, Lee SU, Ishikawa Y, Li M, Williams JC, Wang L, Su L, Suzuki M, Saito TI, Chiba S, Casola S, Yagita H, Teruya-Feldstein J, Tsuzuki S, Bhatia R, Maeda T.
J Clin Invest. 2011 Jul 1;121(7):2583-98. doi: 10.1172/JCI45682. Epub 2011 Jun 6.
PMID 21646720
 
Structure of the POZ domain of human LRF, a master regulator of oncogenesis.
Schubot FD, Tropea JE, Waugh DS.
Biochem Biophys Res Commun. 2006 Dec 8;351(1):1-6. Epub 2006 Oct 9.
PMID 17052694
 
Crystal structure of the BTB domain from the LRF/ZBTB7 transcriptional regulator.
Stogios PJ, Chen L, Prive GG.
Protein Sci. 2007 Feb;16(2):336-42. Epub 2006 Dec 22.
PMID 17189472
 
Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.
Tian Z, Wang H, Jia Z, Shi J, Tang J, Mao L, Liu H, Deng Y, He Y, Ruan Z, Li J, Wu Y, Ni B.
Curr Cancer Drug Targets. 2010 Dec;10(8):932-41.
PMID 20879980
 
MicroRNA (miRNA)-mediated interaction between leukemia/lymphoma-related factor (LRF) and alternative splicing factor/splicing factor 2 (ASF/SF2) affects mouse embryonic fibroblast senescence and apoptosis.
Verduci L, Simili M, Rizzo M, Mercatanti A, Evangelista M, Mariani L, Rainaldi G, Pitto L.
J Biol Chem. 2010 Dec 10;285(50):39551-63. Epub 2010 Oct 4.
PMID 20923760
 
Functional identification of LRF as an oncogene that bypasses RASV12-induced senescence via upregulation of CYCLIN E.
Vredeveld LC, Rowland BD, Douma S, Bernards R, Peeper DS.
Carcinogenesis. 2010 Feb;31(2):201-7. Epub 2009 Nov 25.
PMID 19942610
 
Cloning and functional analysis of 5'-upstream region of the Pokemon gene.
Yang Y, Zhou X, Zhu X, Zhang C, Yang Z, Xu L, Huang P.
FEBS J. 2008 Apr;275(8):1860-73. Epub 2008 Mar 18.
PMID 18355317
 
Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results.
Zhao ZH, Wang SF, Yu L, Wang J, Chang H, Yan WL, Zhang J, Fu K.
Lung Cancer. 2008b Oct;62(1):113-9. Epub 2008 Jun 11.
PMID 18550205
 
Pro-oncogene Pokemon promotes breast cancer progression by upregulating survivin expression.
Zu X, Ma J, Liu H, Liu F, Tan C, Yu L, Wang J, Xie Z, Cao D, Jiang Y.
Breast Cancer Res. 2011 Mar 10;13(2):R26. [Epub ahead of print]
PMID 21392388
 
Global mapping of ZBTB7A transcription factor binding sites in HepG2 cells.
Zu X, Yu L, Sun Y, Tian J, Liu F, Sun Q, He S, Sun G, Luo W, Jiang Y.
Cell Mol Biol Lett. 2010 Jun;15(2):260-71. Epub 2010 Mar 19.
PMID 20336405
 

Citation

This paper should be referenced as such :
Apostolopoulou, K ; Pateras, IS ; Kotsinas, A ; Gorgoulis, VG
ZBTB7A (zinc finger, BTB domain containing 7A)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1058-1066.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ZBTB7AID42863ch19p13.html


External links

Nomenclature
HGNC (Hugo)ZBTB7A   18078
Cards
AtlasZBTB7AID42863ch19p13
Entrez_Gene (NCBI)ZBTB7A  51341  zinc finger and BTB domain containing 7A
AliasesFBI-1; FBI1; LRF; TIP21; 
ZBTB7; ZNF857A; pokemon
GeneCards (Weizmann)ZBTB7A
Ensembl hg19 (Hinxton)ENSG00000178951 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000178951 [Gene_View]  chr19:4043304-4065529 [Contig_View]  ZBTB7A [Vega]
ICGC DataPortalENSG00000178951
TCGA cBioPortalZBTB7A
AceView (NCBI)ZBTB7A
Genatlas (Paris)ZBTB7A
WikiGenes51341
SOURCE (Princeton)ZBTB7A
Genetics Home Reference (NIH)ZBTB7A
Genomic and cartography
GoldenPath hg38 (UCSC)ZBTB7A  -     chr19:4043304-4065529 -  19p13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ZBTB7A  -     19p13.3   [Description]    (hg19-Feb_2009)
EnsemblZBTB7A - 19p13.3 [CytoView hg19]  ZBTB7A - 19p13.3 [CytoView hg38]
Mapping of homologs : NCBIZBTB7A [Mapview hg19]  ZBTB7A [Mapview hg38]
OMIM605878   
Gene and transcription
Genbank (Entrez)AF000561 AF097916 AL390151 BC019108 BC080608
RefSeq transcript (Entrez)NM_001317990 NM_015898
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ZBTB7A
Cluster EST : UnigeneHs.591384 [ NCBI ]
CGAP (NCI)Hs.591384
Alternative Splicing GalleryENSG00000178951
Gene ExpressionZBTB7A [ NCBI-GEO ]   ZBTB7A [ EBI - ARRAY_EXPRESS ]   ZBTB7A [ SEEK ]   ZBTB7A [ MEM ]
Gene Expression Viewer (FireBrowse)ZBTB7A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)51341
GTEX Portal (Tissue expression)ZBTB7A
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95365   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95365  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95365
Splice isoforms : SwissVarO95365
PhosPhoSitePlusO95365
Domaine pattern : Prosite (Expaxy)BTB (PS50097)    ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)BTB/POZ_dom    SKP1/BTB/POZ    Znf_C2H2    Znf_C2H2-like    Znf_C2H2/integrase_DNA-bd   
Domain families : Pfam (Sanger)BTB (PF00651)    zf-C2H2 (PF00096)   
Domain families : Pfam (NCBI)pfam00651    pfam00096   
Domain families : Smart (EMBL)BTB (SM00225)  ZnF_C2H2 (SM00355)  
Conserved Domain (NCBI)ZBTB7A
DMDM Disease mutations51341
Blocks (Seattle)ZBTB7A
PDB (SRS)2IF5    2NN2   
PDB (PDBSum)2IF5    2NN2   
PDB (IMB)2IF5    2NN2   
PDB (RSDB)2IF5    2NN2   
Structural Biology KnowledgeBase2IF5    2NN2   
SCOP (Structural Classification of Proteins)2IF5    2NN2   
CATH (Classification of proteins structures)2IF5    2NN2   
SuperfamilyO95365
Human Protein AtlasENSG00000178951
Peptide AtlasO95365
HPRD10433
IPIIPI00026317   IPI00024943   
Protein Interaction databases
DIP (DOE-UCLA)O95365
IntAct (EBI)O95365
FunCoupENSG00000178951
BioGRIDZBTB7A
STRING (EMBL)ZBTB7A
ZODIACZBTB7A
Ontologies - Pathways
QuickGOO95365
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  DNA binding  protein binding  nucleus  transcription, DNA-templated  multicellular organism development  cell differentiation  histone acetyltransferase binding  negative regulation of transcription, DNA-templated  metal ion binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  DNA binding  protein binding  nucleus  transcription, DNA-templated  multicellular organism development  cell differentiation  histone acetyltransferase binding  negative regulation of transcription, DNA-templated  metal ion binding  
Pathways : BIOCARTAB Cell Survival Pathway [Genes]   
NDEx NetworkZBTB7A
Atlas of Cancer Signalling NetworkZBTB7A
Wikipedia pathwaysZBTB7A
Orthology - Evolution
OrthoDB51341
GeneTree (enSembl)ENSG00000178951
Phylogenetic Trees/Animal Genes : TreeFamZBTB7A
HOVERGENO95365
HOGENOMO95365
Homologs : HomoloGeneZBTB7A
Homology/Alignments : Family Browser (UCSC)ZBTB7A
Gene fusions - Rearrangements
Fusion : MitelmanTGFBR2/ZBTB7A [3p24.1/19p13.3]  [t(3;19)(p24;p13)]  
Fusion : MitelmanZBTB7A/TNK1 [19p13.3/17p13.1]  [t(17;19)(p13;p13)]  
Fusion: TCGAZBTB7A 19p13.3 TNK1 17p13.1 LAML
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerZBTB7A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ZBTB7A
dbVarZBTB7A
ClinVarZBTB7A
1000_GenomesZBTB7A 
Exome Variant ServerZBTB7A
ExAC (Exome Aggregation Consortium)ZBTB7A (select the gene name)
Genetic variants : HAPMAP51341
Genomic Variants (DGV)ZBTB7A [DGVbeta]
DECIPHERZBTB7A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisZBTB7A 
Mutations
ICGC Data PortalZBTB7A 
TCGA Data PortalZBTB7A 
Broad Tumor PortalZBTB7A
OASIS PortalZBTB7A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICZBTB7A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDZBTB7A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ZBTB7A
DgiDB (Drug Gene Interaction Database)ZBTB7A
DoCM (Curated mutations)ZBTB7A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ZBTB7A (select a term)
intoGenZBTB7A
NCG5 (London)ZBTB7A
Cancer3DZBTB7A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605878   
Orphanet
MedgenZBTB7A
Genetic Testing Registry ZBTB7A
NextProtO95365 [Medical]
TSGene51341
GENETestsZBTB7A
Target ValidationZBTB7A
Huge Navigator ZBTB7A [HugePedia]
snp3D : Map Gene to Disease51341
BioCentury BCIQZBTB7A
ClinGenZBTB7A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD51341
Chemical/Pharm GKB GenePA134885165
Clinical trialZBTB7A
Miscellaneous
canSAR (ICR)ZBTB7A (select the gene name)
Probes
Litterature
PubMed75 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineZBTB7A
EVEXZBTB7A
GoPubMedZBTB7A
iHOPZBTB7A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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