Abl gene
Encyclopedia
V-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein
that, in humans, is encoded by the ABL1 gene
located on chromosome 9.
that has been implicated in processes of cell differentiation, cell division
, cell adhesion
, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain
, and deletion of the SH3 domain turns ABL1 into an oncogene
. The t(9;22) translocation results in the head-to-tail fusion
of the BCR
and ABL1 genes, leading to a fusion gene
present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation
, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.
(CML). In CML, the gene is activated by being translocated within the BCR
(breakpoint cluster region) gene
on chromosome 22. This new fusion gene
, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene
with the BCR gene in the Philadelphia chromosome
, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia
forms. The BCR-ABL transcript encodes a tyrosine kinase
, which activates mediators of the cell cycle
regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate
, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle
. Second generation BCR-ABL tyrosine-kinase inhibitor
s are also under development
to inhibit BCR-ABL mutants resistant to imatinib.
with RAD9A
, YTHDC1
, TrkA
, NCK1
, Retinoblastoma protein
, RAD51
, Catalase
, PSTPIP1
, ABI2
, DOK1
, ABL2
, PAG1
, BRCA1
, BCAR1
, NEDD9
, CRKL
, PAK2
, SORBS2
, Mdm2
, SHC1
, Ataxia telangiectasia mutated
, EPH receptor B2
, GRB10
, Spectrin, alpha 1, SPTAN1
, Grb2
, TERF1
, VAV1
, RYBP
, Mammalian target of rapamycin
, BCR gene
, Cbl gene
, P73
, GPX1
, RFX1
and ABI1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that, in humans, is encoded by the ABL1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
located on chromosome 9.
Function
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
that has been implicated in processes of cell differentiation, cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, cell adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
, and deletion of the SH3 domain turns ABL1 into an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. The t(9;22) translocation results in the head-to-tail fusion
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
of the BCR
BCR gene
The BCR gene is one of the two genes in the bcr-abl complex, which is associated with the Philadelphia chromosome.-Pathology:...
and ABL1 genes, leading to a fusion gene
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.
Clinical significance
Mutations in the ABL1 gene are associated with chronic myelogenous leukemiaChronic myelogenous leukemia
Chronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
(CML). In CML, the gene is activated by being translocated within the BCR
BCR gene
The BCR gene is one of the two genes in the bcr-abl complex, which is associated with the Philadelphia chromosome.-Pathology:...
(breakpoint cluster region) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on chromosome 22. This new fusion gene
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene
Fusion gene
A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
with the BCR gene in the Philadelphia chromosome
Philadelphia chromosome
Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia . It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t...
, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
forms. The BCR-ABL transcript encodes a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
, which activates mediators of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate
Imatinib
Imatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Second generation BCR-ABL tyrosine-kinase inhibitor
Bcr-Abl tyrosine-kinase inhibitor
Bcr-Abl tyrosine-kinase inhibitors are the first-line therapy for most patients with chronic myelogenous leukemia . In more than 90% cases CML is caused by chromosomal abnormality resulting in the formation of a so-called Philadelphia chromosome...
s are also under development
to inhibit BCR-ABL mutants resistant to imatinib.
Interactions
Abl gene has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with RAD9A
RAD9A
Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the RAD9A gene.-Interactions:RAD9A has been shown to interact with RAD17, HDAC1, TOPBP1, RAD1 homolog, BCL2-like 1, Bcl-2, Androgen receptor, DNAJC7, HUS1 and Abl gene.-Further reading:...
, YTHDC1
YTHDC1
YTH domain-containing protein 1 is a protein that in humans is encoded by the YTHDC1 gene.-Interactions:YTHDC1 has been shown to interact with Emerin, C-src tyrosine kinase, KHDRBS1 and Abl gene.-Further reading:...
, TrkA
TrkA
High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein that in humans is encoded by the NTRK1 gene....
, NCK1
NCK1
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
, Retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
, RAD51
RAD51
RAD51 is a human gene. The protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA and yeast Rad51...
, Catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
, PSTPIP1
PSTPIP1
Proline-serine-threonine phosphatase-interacting protein 1 is an enzyme that in humans is encoded by the PSTPIP1 gene.-Interactions:PSTPIP1 has been shown to interact with PTPN12, PTPN18, BZW1, Abl gene, Wiskott-Aldrich syndrome protein and CD2....
, ABI2
ABI2
Abl interactor 2 also known as Abelson interactor 2 is a protein that in humans is encoded by the ABI2 gene.-Interactions:ABI2 has been shown to interact with ABL1,ADAM19, and TRIM32.-Further reading:...
, DOK1
DOK1
Docking protein 1 is a protein that in humans is encoded by the DOK1 gene.-Interactions:DOK1 has been shown to interact with RET proto-oncogene, SH2D1A, LYN, RAS p21 protein activator 1, INPP5D, CD117, SHC1, Abl gene and TEC.-Further reading:...
, ABL2
ABL2
Tyrosine-protein kinase ABL2 also known as Abelson-related gene is an enzyme that in humans is encoded by the ABL2 gene.- Function :...
, PAG1
PAG1
Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 is a protein that in humans is encoded by the PAG1 gene.-Interactions:...
, BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
, BCAR1
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.-External links:* Info with links in the...
, NEDD9
NEDD9
Enhancer of filamentation 1 is a protein that in humans is encoded by the NEDD9 gene.-Interactions:NEDD9 has been shown to interact with ID2, LYN, NCK1, MICAL1, CDH1, Abl gene, PTK2, CRKL, CRK and Mothers against decapentaplegic homolog 3....
, CRKL
CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
, PAK2
PAK2
Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.-Interactions:PAK2 has been shown to interact with SH3KBP1, CDC42 and Abl gene.-External links:* Info with links in the...
, SORBS2
SORBS2
Sorbin and SH3 domain-containing protein 2 is a protein that in humans is encoded by the SORBS2 gene.-Interactions:SORBS2 has been shown to interact with PTK2B, Cbl gene, ABL2 and Abl gene.-Further reading:...
, Mdm2
Mdm2
Mdm2 is an important negative regulator of the p53 tumor suppressor. It is the name of a gene as well as the protein encoded by that gene. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and an inhibitor of...
, SHC1
SHC1
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
, Ataxia telangiectasia mutated
Ataxia telangiectasia mutated
Ataxia telangiectasia mutated is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis...
, EPH receptor B2
EPH receptor B2
Ephrin type-B receptor 2 is a protein that in humans is encoded by the EPHB2 gene.Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system...
, GRB10
GRB10
Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the GRB10 gene.- Function :...
, Spectrin, alpha 1, SPTAN1
SPTAN1
Spectrin alpha chain, brain is a protein that in humans is encoded by the SPTAN1 gene.The spectrins are a family of widely-distributed cytoskeletal proteins which are involved in actin crosslinking. The protein enocoded by this gene is a spectrin alpha-chain which heterodimerizes with...
, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, TERF1
TERF1
Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.-Interactions:TERF1 has been shown to interact with SALL1, MAPRE1, NME1, TNKS2, Ataxia telangiectasia mutated, TINF2, TNKS, PINX1 and Abl gene....
, VAV1
VAV1
Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...
, RYBP
RYBP
RING1 and YY1-binding protein is a protein that in humans is encoded by the RYBP gene.-Interactions:RYBP has been shown to interact with RING1, YY1, Caspase 10, E2F3, E2F2, Mdm2, Abl gene and CBX2.-Further reading:...
, Mammalian target of rapamycin
Mammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
, BCR gene
BCR gene
The BCR gene is one of the two genes in the bcr-abl complex, which is associated with the Philadelphia chromosome.-Pathology:...
, Cbl gene
Cbl gene
Cbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination...
, P73
P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
, GPX1
GPX1
Glutathione peroxidase 1 is an enzyme that in humans is encoded by the GPX1 gene.-Further reading:...
, RFX1
RFX1
MHC class II regulatory factor RFX1 is a protein that in humans is encoded by the RFX1 gene.-Further reading:...
and ABI1
ABI1
Abl interactor 1 also known as Abelson interactor 1 is a protein that in humans is encoded by the ABI1 gene.- Function :Abl interactor 1 has been found to form a complex with EPS8 and SOS1, and is thought to be involved in the transduction of signals from Ras to Rac...
.
Regulation
There is some evidence that the expression of Abl is regulated by the microRNA miR-203.Further reading
- Clark, Stevens. "Publications." Research Papers 1986-1989.
- Dunitz, Martin. "Chronic Myeloid Leukaemia" 2001. Taylor & Francis, Limited. Published online via Ebrary.com
- Scott K Shore, Ramana V Tantravahi and E Premkumar Reddy. "Transforming pathways activated by the v-Abl tyrosine kinase" 9 Dec. 2002.
External links
(ABL)- Drosophila Abl tyrosine kinase - The Interactive Fly
- ABL1 Info with links in the Cell Migration Gateway
- ABL1 on the Atlas of Genetics and OncologyAtlas of Genetics and Cytogenetics in Oncology and HaematologyThe Atlas of Genetics and Cytogenetics in Oncology and Haematology is a collection of resources on genes, chromosomes anomalies, leukemias, solid tumours, and cancer-prone diseases...