SALL4
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Location (UCSC) | Chr 20: 51.78 – 51.8 Mb | Chr 2: 168.59 – 168.61 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4.
Structure, interaction partners, and DNA binding activity
SALL4 contains one zinc finger in its amino (N-) terminus and three clusters of zinc fingers that each coordinates zinc with two cysteines and two histidines (Cys2His2-type) that potentially confer nucleic acid binding activity. SALL4B lacks two of the zinc finger clusters found in the A isoform. Although it remains unclear which zinc finger cluster is responsible for SALL4’s DNA binding property
Different SALL family members can form hetero- or homodimers via their conserved glutamine (Q)-rich region.
In mouse ESCs, Sall4 was found to bind the essential stem cell factor, octamer-binding transcription factor 4 (
Expression and role in stem cells and development
In mouse embryos, SALL4 expression is detectable as early as the two-cell stage. Its expression persists through 8- and 16-cell stages to the blastocyst, where it is found in some cells of the trophectoderm and inner cell mass (ICM), from which mouse ESCs are derived.[30] SALL4 is an important factor for maintaining the “stemness” of ESCs of both mouse and human origin, since loss of Sall4 leads to differentiation of these pluripotent cells down the trophectoderm lineage.[17][30][31] This is possibly due to down-regulation of Pou5f1 (encoding Oct4) expression and up-regulation of caudal-type homeobox 2 (Cdx2) gene expression.[31] Sall4 is part of the transcriptional regulatory network that includes other pluripotent factors such as Oct4, Nanog, and Sox2[32][33] Because of its important role in early development, genetically mutated mice without functioning SALL4 die early on at the peri-implantation stage, while heterozygous mice have neural, kidney, heart defects and limb abnormalities.[17][25][34]
Clinical significance
The various SALL4-null mouse models mimic human mutations in the SALL4 gene, which were shown to cause developmental problems in patients with Okihiro/Duane-Radial-ray syndrome.[35][36] These individuals frequently have family history of hand malformation and eye movement disorders.
SALL4 expression is low to undetectable in most adult tissues with the exception of germ cells and human blood progenitor cells.
In breast cancer, Signal transducer and activator of transcription 3 (STAT3) has been reported to directly activate SALL4 expression.[51] Furthermore, canonical Wnt signaling has been proposed to activate SALL4 gene expression in both development[52][53] and in cancer.[28] In leukemia, the mechanism of SALL4 function is better characterized; mice with over-expression of human SALL4 develop myelodysplatic syndromes (MDS)-like symptoms and eventually AML.[28] This is consistent with high level of SALL4 expression correlating with high-risk MDS patients.[54][55] Further elucidating its tumorigenesis function, knocking down SALL4 expression with short hairpin-RNA in leukemic cells or treating these cells with a peptide that mimics the N-12aa of SALL4 to inhibit its interaction with the NuRD complex both result in cell death.[13][44] These suggest the primary cancer-maintaining property of SALL4 is mediated through its transcriptional repressing function. These observations have led to growing interest in SALL4 as both a diagnostic tool as well as target in cancer therapy. For example, in solid tumors such as germ cell tumors, SALL4 protein expression has become a standard diagnostic biomarker.[56]
Notes
Wikidata Q28273464 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000101115 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027547 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: SALL4 sal-like 4 (Drosophila)".
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Further reading
- Sweetman D, Münsterberg A (May 2006). "The vertebrate spalt genes in development and disease" (PDF). Developmental Biology. 293 (2): 285–293. S2CID 45268563.
- Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W (Nov 2002). "Okihiro syndrome is caused by SALL4 mutations". Human Molecular Genetics. 11 (23): 2979–2987. PMID 12393809.
- Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC (Nov 2002). "Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family". American Journal of Human Genetics. 71 (5): 1195–1199. PMID 12395297.
- Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W (Jul 2003). "Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy". Journal of Medical Genetics. 40 (7): 473–478. PMID 12843316.
- Borozdin W, Wright MJ, Hennekam RC, Hannibal MC, Crow YJ, Neumann TE, Kohlhase J (Aug 2004). "Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum". Journal of Medical Genetics. 41 (8): e102. PMID 15286162.
- Kohlhase J, Holmes LB (Aug 2004). "Mutations in SALL4 in malformed father and daughter postulated previously due to reflect mutagenesis by thalidomide". Birth Defects Research. Part A, Clinical and Molecular Teratology. 70 (8): 550–551. PMID 15329836.
- Borozdin W, Boehm D, Leipoldt M, Wilhelm C, Reardon W, Clayton-Smith J, Becker K, Mühlendyck H, Winter R, Giray O, Silan F, Kohlhase J (Sep 2004). "SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism". Journal of Medical Genetics. 41 (9): e113. PMID 15342710.
- Wabbels BK, Lorenz B, Kohlhase J (Dec 2004). "No evidence of SALL4-mutations in isolated sporadic duane retraction "syndrome" (DURS)". American Journal of Medical Genetics Part A. 131 (2): 216–218. S2CID 35230437.
- Kohlhase J, Chitayat D, Kotzot D, Ceylaner S, Froster UG, Fuchs S, Montgomery T, Rösler B (Sep 2005). "SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders". Human Mutation. 26 (3): 176–183. S2CID 32696827.
- Miertus J, Borozdin W, Frecer V, Tonini G, Bertok S, Amoroso A, Miertus S, Kohlhase J (Mar 2006). "A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome". Human Genetics. 119 (1–2): 154–161. S2CID 39709020.
- Terhal P, Rösler B, Kohlhase J (Feb 2006). "A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation". American Journal of Medical Genetics Part A. 140 (3): 222–226. S2CID 27878708.
- Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L (Oct 2006). "SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice". Blood. 108 (8): 2726–2735. PMID 16763212.
- Paradisi I, Arias S (Feb 2007). "IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus". American Journal of Medical Genetics Part A. 143 (4): 326–332. S2CID 22880350.
- Habano W, Sugai T, Jiao YF, Nakamura S (Oct 2007). "Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy". International Journal of Cancer. 121 (7): 1487–1493. S2CID 9573680.
- Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y (Jun 2007). "Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells". Proceedings of the National Academy of Sciences of the United States of America. 104 (25): 10494–10499. PMID 17557835.