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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SIL (SCL/TAL1 interrupting locus) Asher Castiel, Shai Izraeli Department of Pediatric Hemato-Oncology, Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel Published in Atlas Database: October 2005 Online updated version: http://AtlasGeneticsOncology.org/Genes/SILID524ch1p32.html DOI: 10.4267/2042/38294 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology Expression Identity SIL is an immediate early gene, with ubiquitous expression in proliferating cells and during early embryonic development. SIL protein levels peak during mitosis and are degraded on transition to G1. SIL is phosphorylated in mitosis. It is expressed in multiple cancers. In lung cancer its expression correlates with the expression of mitotic checkpoint genes. Hugo: STIL Other names: TAL1 (SCL) interrupting locus Location: 1p32 Local order: UMP-CMPK (47511608-47556531); SIL (47427869-47491842); TAL1 (47393984-47407363). Note: 47,427,869 bp from pter; End: 47,491,842 bp from pter; Size: 63,973 bases; Orientation: minus strand. Localisation Cytosolic protein. DNA/RNA Function Description SIL knockout mouse embryos die in utero displaying holopresencephaly, randomized left/right asymmetry and marked apoptosis of the neural folds. Genetic evidence showed that SIL is required for the Sonic Hedgehog response pathway. SIL phosphorylation and interactions with PIN1 is required for maintenance of the mitotic checkpoint. 18 exons distributed over 70 kb. 5' portion of the gene demonstrating alternate exon utilization. Protein Description Homology 1287 amino acids, 148 KDa protein which is highly conserved in vertebrates only. No homologies to known protein motifs except for conserved Serin/Threonine phosporylation sites. There is no homology to other known proteins. Genomic structure of SIL. EcoRI sites (R) are indicated. Exons are as shown; the smaller exons are not drawn to scale. Atlas Genet Cytogenet Oncol Haematol. 2006;10(2) 97 SIL (SCL/TAL1 interrupting locus) Castiel A, Izraeli S Schematic representation of SIL/SCL fusion mRNA. The germ line SIL (solid boxes) and SCL (open boxes) genomic structures are shown. The deletion breakpoints are indicated with arrows. The SIL/SCL genomic rearrangement is indicated below. The SIL/SCL fusion mRNA is formed by SIL exon 1 (solid box) splicing to SCL exon 3 (open box) in a head-to-tail fashion. cell lines (Dami-acute megakaryocytic, and K562erythroid blast crisis of chronic myeloid leukemia). Disease High expression in non-small cell lung cancer (NSCLC). In addition, high expression levels in lung adenocarcinoma, lung squamous carcinoma and lung small cell carcinoma. Prognosis SIL expression is associated with cell proliferation. In lung cancer, SIL overexpression is correlated with high mitotic activity. Mutations Note: No mutations were found in families with hereditary holoprosencephaly. Implicated in SIL- TAL1 (SCL) fusion Note: A submicroscopic deletions fuses the promoter of SIL to TAL1 to induce an abnormal expression of TAL1. Disease T-cell ALL. This TAL1-SIL fusion transcript is found in approximately 25% of T-ALL patients. Cytogenetics Normal karyotype. Hybrid/Mutated Gene The promoter region of the SCL gene, a hematopoietic transcription factor, and the coding region of the SIL gene are deleted. The molecular result of this SIL/SCL rearrangement is an interstitial deletion on chromosome 1 that juxtaposes the 5' portion of the SIL gene to the coding region of the SCL gene. A SIL/SCL fusion mRNA is produced, with SIL exon 1 splicing to SCL exon 3 in a head-to-tail fashion. Because these are both 5' untranslated region (UTR) exons, the net result is that SIL promoter and enhancer elements drive the expression of a full length SCL gene product. References Aplan PD, Lombardi DP, Ginsberg AM, Cossman J, Bertness VL, Kirsch IR. Disruption of the human SCL locus by 'illegitimate' V-(D)-J recombinase activity. Science 1990 Dec 7;250(4986):1426-1429. Peter D. Aplan, Donald P. Lombardi, Ilan R. Kirsch. Structural Characterization of SIL, a Gene Frequently Disrupted in T-Cell Acute Lymphoblastic Leukemia. Mol Cell Biol 1991 Nov;11(11):5462-5469. Aplan PD, Lombardi DP, Reaman GH, Sather HN, Hammond GD, Kirsch IR. Involvement of the putative hematopoietic transcription factor SCL in T-cell acute lymphoblastic leukemia. Blood 1992;79(5):1327-1333. Izraeli S, Colaizzo-Anas T, Bertness VL, Mani K, Aplan PD, Kirsch IR. Expression of the SIL gene is correlated with growth induction and cellular proliferation. Cell Growth Differ 1997;8(11):1171-1179. Izraeli S, Lowe LA, Bertness VL, Good DJ, Dorward DW, Kirsch IR, Kuehn MR. The SIL gene is required for mouse embryonic axial development and left-right specification. Nature 1999 Jun 17;399(6737):691-694. SIL overexpression in lung cancer Note: SIL is also overexpressed in various solid tumors (melanoma, lymphoma, ovary cancer, breast cancer colon cancer lung and prostate cancer) and leukemic Atlas Genet Cytogenet Oncol Haematol. 2006;10(2) Izraeli S, Lowe LA, Bertness VL, Campaner S, Hahn H, Kirsch IR, Kuehn MR. Genetic evidence that Sil is required for the Sonic Hedgehog response pathway. Genesis 2001;31(2):7277. 98 SIL (SCL/TAL1 interrupting locus) Castiel A, Izraeli S Karkera JD, Izraeli S, Roessler E, Dutra A, Kirsch I, Muenke M. The genomic structure, chromosomal localization, and analysis of SIL as a candidate gene for holoprosencephaly. Cytogenet Genome Res 2002;97(1-2):62-67. overexpression in lung cancer characterizes tumors with increased mitotic activity. Oncogene 2004 Jul 8;23(31):53715377. Campaner S, Kaldis P, Izraeli S, Kirsch IR. Sil phosphorylation in a Pin1 binding domain affects the duration of the spindle checkpoint. Mol Cell Biol 2005 Aug;25(15):6660-6672. Colaizzo-Anas T, P. D. Aplan. Cloning and characterization of the SIL promoter. Biochim Biophys Acta - Gene Structure and Expression 2003;1625(2):207-213. This article should be referenced as such: Castiel A, Izraeli S. SIL (SCL/TAL1 interrupting locus). Atlas Genet Cytogenet Oncol Haematol.2006;10(2):97-99. Erez A, Perelman M, Hewitt SM, Cojacaru G, Goldberg I, Shahar I, Yaron P, Muler I, Campaner S, Amariglio N, Rechavi G, Kirsch IR, Krupsky M, Kaminski N, Izraeli S. Sil Atlas Genet Cytogenet Oncol Haematol. 2006;10(2) 99