ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)

Identity

Other names	ABL
Hugo	ABL1
Location	9q34.1
Local_order	CAN is more telomeric, TAN1 even more in 9q34.3

DNA/RNA

	DNA diagram
Description	12 exons; 230 kb
Transcription	alternate splicing: 1a and 1b are 5' alternative exons; mRNA of 6 and 7 kb (with 1a and 1b respectively), giving rise to 2 protein of 145 kDa

Protein

	Protein diagram

Description	1130-1143 amino acids; 4 domains: of which are SH (SRC homology) domains; NH2-term -- domain 1: SH3 (where can bind the binding protein BP1, to inhibit SH1 activation) and SH2 (with high affinity towards BCR first exon) -- domain 2: SH1 (with a self-phosphorylable tyrosine) -- 'domain' 3: nuclear localization domain (DNA binding, but not during mitosis) -- domain 4: actin binding (cytoskeleton) --COOH-term; note: 1b (but not the 1a alternative) myristylable allowing anchorage to the membrane
Expression	ubiquitously expressed , c-ABL K/O phenotype is lethal
Localisation	nuclear and cytoplasmic
Function	c-ABL exhibit a permanent nuclear and cytoplasmic shuttling activity, driven by 3 nuclear localisation signals (NLS) and a single nuclear export signal (NES) close to the C-terminal region. Recent data suggest that nuclear and cytoplasmic ABL may have differnet functions. 1- Nuclear c-ABL plays a major role in the regulation of cell death after DNA damage. All DNA damage inducing agents activate nuclear c-ABL kinase in a ATM-dependent manner and in the presence of the p53-homolog p73 protein. The latter is physically associated with c-ABL after DNA damage through the SH3 domain of c-ABL. DNA damage also activates simultanously p53 pathway, leading to the activation of Rb which induces growth arrest and protects cells from apoptosis. The exacts mechanisms of apoptosis induced by c-ABL are unknown. The nuclear entrapment of BCR-ABL has also been shown to induce apoptosis in leukemic cells. 2- Cytoplasmic c-ABL : possible function in adhesion signalling as an efflux of c-ABL from nucleus to the cytoplasm is found in fibroblasts after adhesion.
Homology	SRC homology; like SRC, ABL is one of the tyrosine kinases which are not membrane receptors

Implicated in

Entity	t(9;12)(q34;p12)/ALL --> ETV6-ABL
Disease	common ALL; yet poorly known
Hybrid/Mutated Gene	5' ETV6/TEL from 12p12 - 3' ABL from 9q34
Abnormal Protein	NH2-term Helix Loop Helix from ETV6(TEL) fused to Tyr Kinase from ABL COOH-term; localised in the cytoskeleton.
Oncogenesis	forms HLH-dependent oligomers, which may be critical for Tyr kinase activation; oncogenesis may be comparable to that induced by BCR/ABL
Entity	t(9;22)(q34;q11)/CML --> BCR/ABL
Disease	all CML have a t(9;22), at least at the molecular level (BCR/ABL); phenotype and stem cell origin: multipotent progenitor: t(9;22) is found in all myeloid and B- lineage progenitors
Prognosis	median survival => 4 yrs; alphaIFN therapy or BMT are indicated
Cytogenetics	anomalies additional to the t(9;22) may be found either at diagnosis or during course of the disease, or at the time of acute transformation; mainly: +der(22), +8, i(17q), +19; +21, -Y, -7, -17,+17; variant translocations: t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, karyotypes with apparently normal chromosomes 9 and 22, may be found
	Probe 1132H12 on a case of CML with t(9/22). Note the splitting of the probe, evident also on interphase nuclei - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
Hybrid/Mutated Gene	see below
Abnormal Protein	see below
Oncogenesis	see below
Entity	t(9;22)(q34;q11)/ALL --> BCR/ABL
Disease	most often CD 10+ ALL; frequent CNS involvement
Prognosis	is very poor (BMT is indicated); the breakpiont in M-bcr or in m-bcr (see below) does not seem to have impact on prognosis
Cytogenetics	the chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and ANLL cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML
Hybrid/Mutated Gene	see below
Abnormal Protein	see below
Oncogenesis	see below
Entity	t(9;22)(q34;q11)/ANLL --> BCR/ABL
Disease	ANLL mostly M1 or M2 ANL
Prognosis	is very poor
Cytogenetics	the chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: similar to what is found in CML
Hybrid/Mutated Gene	see below
Abnormal Protein	see below
Oncogenesis	see below
Hybrid/Mutated Gene	BCR/ABL the crucial event lies on der(22), id est 5' BCR - 3' ABL hybrid gene is the crucial one, while ABL/BCR may or may not be expressed; breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b or 3' of 1a, but always 5' of exon 2; breakpoint in BCR is either: 1- in a region called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M- bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 KDa chimeric protein (P210); this is found in (most cases of) CML, and in half cases of ALL or ANLL HYBRID_GENE 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190); this is found in half of the cases of ALL or ANLL 3- A breakpoint in the exon 19 of BCR (designed as micro-bcr) with fusion to abl sequences (a2) has been in neutrophilic CML, with presence of a larger protein (P230).
Abnormal Protein	BCR/ABL P210 comprises the first 902 or 927 amino acids from BCR, P190 only the 427 N-term from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear
Oncogenesis	BCR/ABL has a cytoplasmic localization role and all three BCR-ABL fusion proteins have been shown to exhibit oncogenic potential. All three hybrid proteins have increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain,which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated; oncogenesis 1- proliferation is induced through activation by BCR/ABL of RAS signal transduction pathway, PI3-K (phosphatidyl inositol 3' kinase) pathway, and MYC; 2- BCR/ABL inhibits apoptosis; 3- BCR/ABL provokes cell adhesive abnormalities

Breakpoints

External links

	Nomenclature
Hugo	ABL1
GDB	ABL1
Entrez_Gene	ABL1  25  c-abl oncogene 1, receptor tyrosine kinase
	Cards
Atlas	ABL
GeneCards	ABL1
Ensembl	ABL1 [Search_View]   ENSG00000097007 [Gene_View]
Genatlas	ABL1
GeneLynx	ABL1
eGenome	ABL1
euGene	25
	Genomic and cartography
GoldenPath	ABL1  -  9q34.1   chr9:132579089-132752881 +  9q34.1   [Description]    (hg18-Mar_2006)
Ensembl	ABL1 - 9q34.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	ABL1
	Gene and transcription
Genbank	AA524892 [ ENTREZ ]
Genbank	AB209456 [ ENTREZ ]
Genbank	AB209642 [ ENTREZ ]
Genbank	AF113911 [ ENTREZ ]
Genbank	AJ131466 [ ENTREZ ]
RefSeq	NM_005157 [ SRS ]    NM_005157 [ ENTREZ ]
RefSeq	NM_007313 [ SRS ]    NM_007313 [ ENTREZ ]
RefSeq	AC_000052 [ SRS ]    AC_000052 [ ENTREZ ]
RefSeq	AC_000141 [ SRS ]    AC_000141 [ ENTREZ ]
RefSeq	NC_000009 [ SRS ]    NC_000009 [ ENTREZ ]
RefSeq	NT_035014 [ SRS ]    NT_035014 [ ENTREZ ]
RefSeq	NW_001839240 [ SRS ]    NW_001839240 [ ENTREZ ]
RefSeq	NW_924573 [ SRS ]    NW_924573 [ ENTREZ ]
AceView	ABL1 AceView - NCBI
Unigene	Hs.431048 [ SRS ]    Hs.431048 [ NCBI ]     HS431048 [ spliceNest ]
Fast-db	16214 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P00519 [ SRS]    P00519 [ EXPASY ]     P00519 [ INTERPRO ]
Prosite	PS00107 PROTEIN_KINASE_ATP [ SRS ]    PS00107 PROTEIN_KINASE_ATP [ Expasy ]
Prosite	PS50011 PROTEIN_KINASE_DOM [ SRS ]    PS50011 PROTEIN_KINASE_DOM [ Expasy ]
Prosite	PS00109 PROTEIN_KINASE_TYR [ SRS ]    PS00109 PROTEIN_KINASE_TYR [ Expasy ]
Prosite	PS50001 SH2 [ SRS ]    PS50001 SH2 [ Expasy ]
Prosite	PS50002 SH3 [ SRS ]    PS50002 SH3 [ Expasy ]
Interpro	IPR015015 F_actin_bd [ SRS ]    IPR015015 F_actin_bd [ EBI ]
Interpro	IPR000719 Prot_kinase_core [ SRS ]    IPR000719 Prot_kinase_core [ EBI ]
Interpro	IPR017441 Protein_kinase_ATP_bd_CS [ SRS ]    IPR017441 Protein_kinase_ATP_bd_CS [ EBI ]
Interpro	IPR000980 SH2 [ SRS ]    IPR000980 SH2 [ EBI ]
Interpro	IPR001452 SH3 [ SRS ]    IPR001452 SH3 [ EBI ]
Interpro	IPR001245 Tyr_pkinase [ SRS ]    IPR001245 Tyr_pkinase [ EBI ]
Interpro	IPR008266 Tyr_pkinase_AS [ SRS ]    IPR008266 Tyr_pkinase_AS [ EBI ]
CluSTr	P00519
Pfam	PF08919 F_actin_bind [ SRS ]    PF08919 F_actin_bind [ Sanger ]    pfam08919 [ NCBI-CDD ]
Pfam	PF07714 Pkinase_Tyr [ SRS ]    PF07714 Pkinase_Tyr [ Sanger ]    pfam07714 [ NCBI-CDD ]
Pfam	PF00017 SH2 [ SRS ]    PF00017 SH2 [ Sanger ]    pfam00017 [ NCBI-CDD ]
Pfam	PF00018 SH3_1 [ SRS ]    PF00018 SH3_1 [ Sanger ]    pfam00018 [ NCBI-CDD ]
Smart	SM00808 FABD [EMBL]
Smart	SM00252 SH2 [EMBL]
Smart	SM00326 SH3 [EMBL]
Smart	SM00219 TyrKc [EMBL]
Prodom	PD000001 Prot_kinase[INRA-Toulouse]
Prodom	P00519 ABL1_HUMAN [ Domain structure ]   P00519 ABL1_HUMAN  [ sequences sharing at least 1 domain ]
Prodom	PD000001[INRA-Toulouse]
Prodom	P00519 ABL1_HUMAN [ Domain structure ]   P00519 ABL1_HUMAN  [ sequences sharing at least 1 domain ]
Prodom	PD000001[INRA-Toulouse]
Prodom	P00519 ABL1_HUMAN [ Domain structure ]   P00519 ABL1_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P00519
PDB	ABL1 [ SRS ]    ABL1 [ PdbSum ],   ABL1 [ IMB ]   ABL1 [ RSDB ]
HPRD	01809
	Protein Interaction databases
DIP	P00519
IntAct	P00519
	Polymorphism : SNP, mutations, diseases
OMIM	189980    [ map ]
GENECLINICS	189980
SNP	ABL1 [dbSNP-NCBI]
SNP	NM_005157 [SNP-NCI]
SNP	NM_007313 [SNP-NCI]
SNP	ABL1 [GeneSNPs - Utah]  ABL1] [HGBASE - SRS]
HAPMAP	ABL1 [HAPMAP]
COSMIC	ABL1 [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb	ABL1 [Translocation breakpoints In Cancer]
HGMD	ABL1
	General knowledge
Family Browser	ABL1 [UCSC Family Browser]
SOURCE	NM_005157
SOURCE	NM_007313
SMD	Hs.431048
SAGE	Hs.431048
Enzyme	2.7.10.2 [ Enzyme-Expasy ]   2.7.10.2 [ Enzyme-SRS ]   2.7.10.2 [ IntEnz-EBI ]   2.7.10.2 [ BRENDA ]   2.7.10.2 [ KEGG ]   2.7.10.2 [ WIT ]
GO	S-phase-specific transcription in mitotic cell cycle [Amigo]  S-phase-specific transcription in mitotic cell cycle
GO	nucleotide binding [Amigo]  nucleotide binding
GO	magnesium ion binding [Amigo]  magnesium ion binding
GO	molecular_function [Amigo]  molecular_function
GO	DNA binding [Amigo]  DNA binding
GO	non-membrane spanning protein tyrosine kinase activity [Amigo]  non-membrane spanning protein tyrosine kinase activity
GO	receptor activity [Amigo]  receptor activity
GO	ATP binding [Amigo]  ATP binding
GO	cellular_component [Amigo]  cellular_component
GO	nucleus [Amigo]  nucleus
GO	nucleolus [Amigo]  nucleolus
GO	cytoplasm [Amigo]  cytoplasm
GO	cytoskeleton [Amigo]  cytoskeleton
GO	mismatch repair [Amigo]  mismatch repair
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	protein modification process [Amigo]  protein modification process
GO	cell adhesion [Amigo]  cell adhesion
GO	protein C-terminus binding [Amigo]  protein C-terminus binding
GO	biological_process [Amigo]  biological_process
GO	DNA damage response, signal transduction resulting in induction of apoptosis [Amigo]  DNA damage response, signal transduction resulting in induction of apoptosis
GO	kinase activity [Amigo]  kinase activity
GO	transferase activity [Amigo]  transferase activity
GO	peptidyl-tyrosine phosphorylation [Amigo]  peptidyl-tyrosine phosphorylation
GO	actin cytoskeleton organization and biogenesis [Amigo]  actin cytoskeleton organization and biogenesis
GO	manganese ion binding [Amigo]  manganese ion binding
GO	positive regulation of oxidoreductase activity [Amigo]  positive regulation of oxidoreductase activity
KEGG	Cell cycle
KEGG	Axon guidance
PubGene	ABL1
TreeFam	ABL1
CTD	25 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	ABL (9q34) in normal cells (Bari)
Probe	ABL1 Related clones (RZPD - Berlin)
	PubMed
PubMed	302 Pubmed reference(s) in LocusLink

Bibliography

The function of BCR/ABL and related proto-oncogenes.

Gotoh A, Broxmeyer HE

Current opinion in hematology. 1997 ; 4 (1) : 3-11.

PMID 9050373

Molecular insights into the Philadelphia translocation.

Heisterkamp N, Groffen J

Hematologic pathology. 1991 ; 5 (1) : 1-10.

PMID 2050600

The molecular pathology of chronic myelogenous leukaemia.

Kurzrock R, Talpaz M

British journal of haematology. 1991 ; 79 Suppl 1 : 34-37.

PMID 1931706

Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.

Taagepera S, McDonald D, Loeb JE, Whitaker LL, McElroy AK, Wang JY, Hope TJ

Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (13) : 7457-7462.

PMID 9636171

The molecular biology of chronic myeloid leukemia.

Deininger MW, Goldman JM, Melo JV

Blood. 2000 ; 96 (10) : 3343-3356.

PMID 11071626

Regulation of cell death by the Abl tyrosine kinase.

Wang JY

Oncogene. 2000 ; 19 (49) : 5643-5650.

PMID 11114745

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	10-1997	Jean-Loup Huret
Updated	04-2001	Ali G Turhan

Citation

This paper should be referenced as such :

Huret JL . ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. October 1997 . URL : http://AtlasGeneticsOncology.org/Genes/ABL.html

Turhan AG . ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1). Atlas Genet Cytogenet Oncol Haematol. April 2001 . URL : http://AtlasGeneticsOncology.org/Genes/ABL.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Jul 14 17:40:55 2008