ABL

Identity

Other names	ABL1
Hugo	ABL1
Location	9q34.1
	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

External links

	Nomenclature
Hugo	ABL1
GDB	ABL1
LocusLink	ABL1  25
	Cards
Atlas	ABL
GeneCards	ABL1
Ensembl	ABL1 - 9q34.1
CancerGene	ABL1
Genatlas	ABL1
GeneLynx	ABL1
eGenome	ABL1
euGene	25
	Genomic and cartography
GoldenPath	ABL1  -  9q34.1  chr9:128986497-129039105 +   (hg16-July2003)
NCBI	Genes Cyto    Gene Seq [Map View - NCBI]
OMIM	Disease map [OMIM]
HomoloGene	ABL1
	Gene and transcription
Genbank	K00009 [ SRS ]    K00009 [ ENTREZ ]
Genbank	13099 [ SRS ]    13099 [ ENTREZ ]
Genbank	U07563 [ SRS ]    U07563 [ ENTREZ ]
Genbank	14752 [ SRS ]    14752 [ ENTREZ ]
Genbank	14753 [ SRS ]    14753 [ ENTREZ ]
RefSeq	NM_005157 [ SRS ]    NM_005157 [ ENTREZ ]
RefSeq	NM_007313 [ SRS ]    NM_007313 [ ENTREZ ]
RefSeq	NT_035014 [ SRS ]    NT_035014 [ ENTREZ ]
AceView	ABL1 AceView - NCBI
TRASER	ABL1 Traser - Stanford
Unigene	Hs.446504 [ SRS ]    Hs.446504 [ NCBI ]     HS446504 [ spliceNest ]
	Protein : pattern, domain, 3D structure
SwissProt	P00519 [ SRS]    P00519 [ EXPASY ]     P00519 [ INTERPRO ]
Prosite	PS00107 PROTEIN_KINASE_ATP [ SRS ]    PS00107 PROTEIN_KINASE_ATP [ Expasy ]
Prosite	PS00109 PROTEIN_KINASE_TYR [ SRS ]    PS00109 PROTEIN_KINASE_TYR [ Expasy ]
Prosite	PS50011 PROTEIN_KINASE_DOM [ SRS ]    PS50011 PROTEIN_KINASE_DOM [ Expasy ]
Prosite	PS50001 SH2 [ SRS ]    PS50001 SH2 [ Expasy ]
Prosite	PS50002 SH3 [ SRS ]    PS50002 SH3 [ Expasy ]
Interpro	IPR000719 Prot_kinase [ SRS ]    IPR000719 Prot_kinase [ 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	PF00069 pkinase [ SRS ]    PF00069 pkinase [ Sanger ]    pfam00069 [ NCBI-CDD ]
Pfam	PF00017 SH2 [ SRS ]    PF00017 SH2 [ Sanger ]    pfam00017 [ NCBI-CDD ]
Pfam	PF00018 SH3 [ SRS ]    PF00018 SH3 [ Sanger ]    pfam00018 [ NCBI-CDD ]
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	1AB2 [ SRS ]    1AB2 [ PdbSum ],   1AB2 [ IMB ]
PDB	2ABL [ SRS ]    2ABL [ PdbSum ],   2ABL [ IMB ]
PDB	1AWO [ SRS ]    1AWO [ PdbSum ],   1AWO [ IMB ]
PDB	1BBZ [ SRS ]    1BBZ [ PdbSum ],   1BBZ [ IMB ]
PDB	1ABL [ SRS ]    1ABL [ PdbSum ],   1ABL [ IMB ]
PDB	1JU5 [ SRS ]    1JU5 [ PdbSum ],   1JU5 [ IMB ]
Human PSD	ABL1
PubGene	ABL1
	Polymorphism : SNP, mutations, diseases
OMIM	189980    [ map ]
SNP	ABL1 [dbSNP-NCBI]
SNP	NM_005157 [SNP-NCI]
SNP	NM_007313 [SNP-NCI]
SNP	ABL1 [GeneSNPs - Utah]  ABL1 [SNP - CSHL]  ABL1] [HGBASE - SRS]
	General knowledge
Family Browser	ABL1 [UCSC Family Browser]
SOURCE	NM_005157
SOURCE	NM_007313
SMD	Hs.446504
SAGE	Hs.446504
Enzyme	2.7.1.112 [ Enzyme-SRS ]   2.7.1.112 [ Brenda-SRS ]   2.7.1.112 [ KEGG ]   2.7.1.112 [ WIT ]
Amigo	function|protein-tyrosine kinase activity
Amigo	function|ATP binding
Amigo	function|DNA binding
Amigo	process|S-specific transcription in mitotic cell cycle
Amigo	process|DNA damage response, signal transduction resulting in induction of apoptosis
Amigo	process|mismatch repair
Amigo	process|cell growth and/or maintenance
Amigo	process|protein amino acid phosphorylation
Amigo	process|regulation of transcription, DNA-dependent
Amigo	process|intracellular signaling cascade
Amigo	process|regulation of cell cycle
Amigo	component|nucleus
Amigo	function|transferase activity
	Other databases
	Probes
Probe	ABL (9q34) in normal cells (Bari)
Probe	ABL1 Related clones (RZPD - Berlin)
	PubMed
PubMed	1 Pubmed reference(s) in LocusLink

Bibliography

The function of BCR/ABL and related proto-oncogenes

Gotoh A, Broxmeyer HE

Curr Opin Hematol 1997; 4: 3-11

Medline 97196352

Molecular insights into the Philadelphia translocation

Heisterkamp N, Groffen J

Hematol Pathol 1991; 5: 1-10

Medline 91267879

The molecular pathology of chronic myelogenous leukaemia

Kurzrock R, Talpaz M

Br J Haematol 1991; 79 Suppl 1: 34-37

Medline 92031068

Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.

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

Proc Natl Acad Sci USA 1998; 95 : 7457-7462.

Medline 9636171

The molecular biology of chronic myeloid leukemia.

Deininger MWN, Goldman JM, Melo JV

Blood 2000; 96: 3343-3356.

Medline 11071626

Regulation of cell death by the Abl tyrosine kinase.

Wang JYJ .

Oncogene 2000; 19 : 5643-5650.

Medline 11114745

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

CancerGene Bibliographic Citations

Contributor(s)

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

Citation

This paper should be referenced as such :

Huret JL . ABL. Atlas Genet Cytogenet Oncol Haematol. October 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ABL.html

Turhan AG . ABL. Atlas Genet Cytogenet Oncol Haematol. April 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ABL.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Tue Apr 27 17:58:22 MEST 2004