Biology:SALL4

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4.[1][2] The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages.[3][4] There are four human SALL proteins (SALL1, 2, 3, and 4) with structural homology and playing diverse roles in embryonic development, kidney function, and cancer.[5] The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes.[6] It is also known as a key embryonic stem cell (ESC) factor.

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.[7] SALL4 has at least one canonical nuclear localization signal (NLS) with the K-K/R-X-K/R motif in the N-terminal portion of the protein shared among both A and B isoforms (residues 64–67).[8] One report has suggested that with a mutated NLS sequence, SALL4 cannot localize to the nucleus.[8] Through a 12-amino acid sequence in its N-terminus (N-12a.a.), SALL4 binds to retinoblastoma binding protein 4 (RBBP4), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, which also contains chromodomain-helicase-DNA binding proteins (CHD3/4 or Mi-2a/b), metastasis-associated proteins (MTA), methyl-CpG-binding domain proteins (MBD2 or MBD3), and histone deacetylases (HDAC1 and HDAC2).[9][10][11][12] This association allows SALL4 to act as a transcriptional repressor. Accordingly, SALL4 has been shown to localize to heterochromatin regions in cells, for which its last zinc finger cluster (shared between SALL4A and B) is necessary.[13] Beside the NuRD complex, SALL4 is reportedly able to bind to other epigenetic modifiers such as histone lysine-specific demethylase 1 (LSD1), which is frequently associated with the NuRD complex and subsequently gene repression.[14] In addition, SALL4 can also activate gene expression via the recruitment of the mixed lineage leukemia (MLL) protein, which is a homolog of Drosophila Trithorax and yeast Set1 proteins and has histone 3 lysine 4 (H3K4) trimethylation activity.[15] This interaction is best characterized in the co-regulation of HOXA9 gene by SALL4 and MLL in leukemic cells.[15]

In mouse ESCs, Sall4 was found to bind the essential stem cell factor, octamer-binding transcription factor 4 (Oct4), in two separate unbiased mass spectrometry (spec) screens[16][17] Sall4 can also bind other important pluripotency proteins such as Nanog and sex determining region Y (SRY)-box 2 protein (Sox2).[18][19] Together these proteins can affect each other’s expression patterns as well as their own, thus forming a mESC-specific transcriptional regulatory circuit.[20] SALL4 has also been reported to bind T-box 5 protein (Tbx5) in cardiac tissues as well as genetically interact with Tbx5 in mouse limb development.[21] Other binding partners of SALL4 include promyelocytic leukemia zinc finger protein (PLZF) in sperm precursor cells,[22] Rad50 during DNA damage repair,[23] and b-catenin downstream of the Wnt signaling pathway.[24] Since most of these interactions were identified by mass-spec or co-immunoprecipitation, whether they are direct are unknown. Through chromatin immunoprecipitation (ChIP) followed by next-generation sequencing or microarray, some SALL4 targets have been identified.[25] A key verified target gene encodes the enzyme phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN). PTEN is a tumor suppressor that keeps uncontrolled cell growth in check through inducing programmed cell death, or apoptosis. SALL4 binds the PTEN promoter and recruits the NuRD complex to mediate its repression, thus leads to proliferation of cells.[12]

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.[26] 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.[13][26][27] This is possibly due to down-regulation of Pou5f1 (encoding Oct4) expression and up-regulation of caudal-type homeobox 2 (Cdx2) gene expression.[27] Sall4 is part of the transcriptional regulatory network that includes other pluripotent factors such as Oct4, Nanog, and Sox2[28][29] 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.[13][21][30]

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.[31][32] 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.[31][33] However, SALL4 is re-activated and mis-regulated in various cancers[34][35] such as acute myeloid leukemia (AML),[24] B-cell acute lymphocytic leukemia (B-ALL),[36] germ cell tumors,[37] gastric cancer,[38] breast cancer,[39] hepatocellular carcinoma (HCC),[40][41] lung cancer,[42] and glioma.[43] In many of these cancers, SALL4 expression was compared in tumor cells to the normal tissue counterpart, e.g. it is expressed in nearly half of primary human endometrial cancer samples, but not in normal or hyperplastic endometrial tissue samples.[44] Often, SALL4 expression is correlated with worse survival and poor prognosis such as in HCC,[40] or with metastasis such as in endometrial cancer,[44] colorectal carcinoma,[45] and esophageal squamous cell carcinoma.[46] It is unclear how SALL4 expression is de-regulated in malignant cells, but DNA hypomethylation in its intron 1 region has been observed in B-ALL.[36]

In breast cancer, Signal transducer and activator of transcription 3 (STAT3) has been reported to directly activate SALL4 expression.[47] Furthermore, canonical Wnt signaling has been proposed to activate SALL4 gene expression in both development[48][49] and in cancer.[24] 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.[24] This is consistent with high level of SALL4 expression correlating with high-risk MDS patients.[50][51] 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.[9][40] 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.[52]

Notes

References

  1. ↑ "Entrez Gene: SALL4 sal-like 4 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57167. 
  2. ↑ "SALL4, the missing link between stem cells, development and cancer". Gene 584 (2): 111–119. June 2016. doi:10.1016/j.gene.2016.02.019. PMID 26892498. 
  3. ↑ "spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo". The EMBO Journal 13 (1): 168–179. Jan 1994. doi:10.1002/j.1460-2075.1994.tb06246.x. PMID 7905822. 
  4. ↑ "Regulation of Drosophila spalt gene expression". Mechanisms of Development 66 (1–2): 107–118. Aug 1997. doi:10.1016/s0925-4773(97)00103-2. PMID 9376314. 
  5. ↑ "Regulation and function of Spalt proteins during animal development". The International Journal of Developmental Biology 53 (8–10): 1385–1398. 2009. doi:10.1387/ijdb.072408jd. PMID 19247946. 
  6. ↑ "SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders". Human Mutation 26 (3): 176–183. Sep 2005. doi:10.1002/humu.20215. PMID 16086360. 
  7. ↑ "The conserved glutamine-rich region of chick csal1 and csal3 mediates protein interactions with other spalt family members. Implications for Townes-Brocks syndrome". The Journal of Biological Chemistry 278 (8): 6560–6566. Feb 2003. doi:10.1074/jbc.M209066200. PMID 12482848. 
  8. ↑ 8.0 8.1 "Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor". Cell Cycle 13 (9): 1456–1462. 2014. doi:10.4161/cc.28418. PMID 24626181. 
  9. ↑ 9.0 9.1 "Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex". Blood 121 (8): 1413–1421. Feb 2013. doi:10.1182/blood-2012-04-424275. PMID 23287862. 
  10. ↑ "FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1". The EMBO Journal 24 (13): 2367–2378. Jul 2005. doi:10.1038/sj.emboj.7600703. PMID 15920470. 
  11. ↑ "A conserved 12-amino acid motif in Sall1 recruits the nucleosome remodeling and deacetylase corepressor complex". The Journal of Biological Chemistry 281 (33): 23922–23931. Aug 2006. doi:10.1074/jbc.M513461200. PMID 16707490. https://escholarship.org/uc/item/15q6p0q9. 
  12. ↑ 12.0 12.1 "Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex". PLOS ONE 4 (5): e5577. 2009. doi:10.1371/journal.pone.0005577. PMID 19440552. Bibcode: 2009PLoSO...4.5577L. 
  13. ↑ 13.0 13.1 13.2 "The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development". Development 133 (15): 3005–3013. Aug 2006. doi:10.1242/dev.02457. PMID 16790473. 
  14. ↑ "Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells". The Journal of Biological Chemistry 288 (48): 34719–34728. Nov 2013. doi:10.1074/jbc.M113.506568. PMID 24163373. 
  15. ↑ 15.0 15.1 "A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis". The Journal of Clinical Investigation 123 (10): 4195–4207. Oct 2013. doi:10.1172/JCI62891. PMID 24051379. 
  16. ↑ "An Oct4-centered protein interaction network in embryonic stem cells". Cell Stem Cell 6 (4): 369–381. Apr 2010. doi:10.1016/j.stem.2010.02.014. PMID 20362541. 
  17. ↑ "An expanded Oct4 interaction network: implications for stem cell biology, development, and disease". Cell Stem Cell 6 (4): 382–395. 2010. doi:10.1016/j.stem.2010.03.004. PMID 20362542. 
  18. ↑ "Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells". The Journal of Biological Chemistry 281 (34): 24090–24094. Aug 2006. doi:10.1074/jbc.C600122200. PMID 16840789. 
  19. ↑ "Stemness-related factor Sall4 interacts with transcription factors Oct-3/4 and Sox2 and occupies Oct-Sox elements in mouse embryonic stem cells". The Journal of Biological Chemistry 288 (7): 5027–5038. Feb 2013. doi:10.1074/jbc.M112.411173. PMID 23269686. 
  20. ↑ "An extended transcriptional network for pluripotency of embryonic stem cells". Cell 132 (6): 1049–1061. Mar 2008. doi:10.1016/j.cell.2008.02.039. PMID 18358816. 
  21. ↑ 21.0 21.1 "Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart". Nature Genetics 38 (2): 175–183. Feb 2006. doi:10.1038/ng1707. PMID 16380715. 
  22. ↑ "Functional antagonism between Sall4 and Plzf defines germline progenitors". Cell Stem Cell 10 (3): 284–298. Mar 2012. doi:10.1016/j.stem.2012.02.004. PMID 22385656. 
  23. ↑ "Stemness factor Sall4 is required for DNA damage response in embryonic stem cells". The Journal of Cell Biology 208 (5): 513–520. Mar 2015. doi:10.1083/jcb.201408106. PMID 25733712. 
  24. ↑ 24.0 24.1 24.2 24.3 "SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice". Blood 108 (8): 2726–2735. Oct 2006. doi:10.1182/blood-2006-02-001594. PMID 16763212. 
  25. ↑ "SALL4 is a key regulator of survival and apoptosis in human leukemic cells". Blood 112 (3): 805–813. Aug 2008. doi:10.1182/blood-2007-11-126326. PMID 18487508. 
  26. ↑ 26.0 26.1 "Murine inner cell mass-derived lineages depend on Sall4 function". Proceedings of the National Academy of Sciences of the United States of America 103 (44): 16319–16324. Oct 2006. doi:10.1073/pnas.0607884103. PMID 17060609. Bibcode: 2006PNAS..10316319E. 
  27. ↑ 27.0 27.1 "Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1". Nature Cell Biology 8 (10): 1114–1123. Oct 2006. doi:10.1038/ncb1481. PMID 16980957. 
  28. ↑ "A protein interaction network for pluripotency of embryonic stem cells". Nature 444 (7117): 364–368. Nov 2006. doi:10.1038/nature05284. PMID 17093407. Bibcode: 2006Natur.444..364W. 
  29. ↑ "A gene regulatory network in mouse embryonic stem cells". Proceedings of the National Academy of Sciences of the United States of America 104 (42): 16438–16443. Oct 2007. doi:10.1073/pnas.0701014104. PMID 17940043. Bibcode: 2007PNAS..10416438Z. 
  30. ↑ "A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis". Genesis 45 (1): 51–58. Jan 2007. doi:10.1002/dvg.20264. PMID 17216607. 
  31. ↑ 31.0 31.1 "Okihiro syndrome is caused by SALL4 mutations". Human Molecular Genetics 11 (23): 2979–2987. Nov 2002. doi:10.1093/hmg/11.23.2979. PMID 12393809. 
  32. ↑ "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. Nov 2002. doi:10.1086/343821. PMID 12395297. 
  33. ↑ "SALL4 is a key transcription regulator in normal human hematopoiesis". Transfusion 53 (5): 1037–1049. May 2013. doi:10.1111/j.1537-2995.2012.03888.x. PMID 22934838. 
  34. ↑ "SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases". The American Journal of Surgical Pathology 38 (3): 410–420. Mar 2014. doi:10.1097/PAS.0000000000000116. PMID 24525512. 
  35. ↑ "SALL4: an emerging cancer biomarker and target". Cancer Letters 357 (1): 55–62. Feb 2015. doi:10.1016/j.canlet.2014.11.037. PMID 25444934. 
  36. ↑ 36.0 36.1 "Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target". Experimental Hematology 42 (4): 307–316.e8. Apr 2014. doi:10.1016/j.exphem.2014.01.005. PMID 24463278. 
  37. ↑ "SALL4 is a novel diagnostic marker for testicular germ cell tumors". The American Journal of Surgical Pathology 33 (7): 1065–1077. Jul 2009. doi:10.1097/PAS.0b013e3181a13eef. PMID 19390421. 
  38. ↑ "SALL4, a novel marker for human gastric carcinogenesis and metastasis". Oncogene 33 (48): 5491–5500. Nov 2014. doi:10.1038/onc.2013.495. PMID 24276240. 
  39. ↑ "SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer". International Journal of Oncology 38 (4): 933–939. Apr 2011. doi:10.3892/ijo.2011.929. PMID 21274508. 
  40. ↑ 40.0 40.1 40.2 "Oncofetal gene SALL4 in aggressive hepatocellular carcinoma". The New England Journal of Medicine 368 (24): 2266–2276. Jun 2013. doi:10.1056/NEJMoa1300297. PMID 23758232. 
  41. ↑ "Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers". Hepatology 57 (4): 1469–1483. Apr 2013. doi:10.1002/hep.26159. PMID 23175232. 
  42. ↑ "High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases". The American Journal of Surgical Pathology 37 (6): 924–932. Jun 2013. doi:10.1097/PAS.0b013e31827e1e83. PMID 23629442. 
  43. ↑ "The expression of SALL4 in patients with gliomas: high level of SALL4 expression is correlated with poor outcome". Journal of Neuro-Oncology 121 (2): 261–268. Jan 2015. doi:10.1007/s11060-014-1646-4. PMID 25359397. 
  44. ↑ 44.0 44.1 "SALL4 is a new target in endometrial cancer". Oncogene 34 (1): 63–72. Jan 2015. doi:10.1038/onc.2013.529. PMID 24336327. 
  45. ↑ "Role of SALL4 in the progression and metastasis of colorectal cancer". Journal of Biomedical Science 20 (1): 6. Jan 2013. doi:10.1186/1423-0127-20-6. PMID 23363002. 
  46. ↑ "Stemness state regulators SALL4 and SOX2 are involved in progression and invasiveness of esophageal squamous cell carcinoma". Medical Oncology 31 (4): 922. Apr 2014. doi:10.1007/s12032-014-0922-7. PMID 24659265. 
  47. ↑ "Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4". FASEB Journal 23 (5): 1405–1414. May 2009. doi:10.1096/fj.08-117721. PMID 19151334. 
  48. ↑ "Spalt-like 4 promotes posterior neural fates via repression of pou5f3 family members in Xenopus". Development 141 (8): 1683–1693. Apr 2014. doi:10.1242/dev.099374. PMID 24715458. 
  49. ↑ "SALL4 is directly activated by TCF/LEF in the canonical Wnt signaling pathway". Biochemical and Biophysical Research Communications 348 (3): 898–907. Sep 2006. doi:10.1016/j.bbrc.2006.07.124. PMID 16899215. 
  50. ↑ "Overexpression of the novel oncogene SALL4 and activation of the Wnt/beta-catenin pathway in myelodysplastic syndromes". Cancer Genetics and Cytogenetics 194 (2): 119–124. Oct 2009. doi:10.1016/j.cancergencyto.2009.06.006. PMID 19781444. 
  51. ↑ "Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes". Journal of Hematology & Oncology 6 (1): 73. Sep 2013. doi:10.1186/1756-8722-6-73. PMID 24283704. 
  52. ↑ "Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the International Society of Urological Pathology consensus conference". The American Journal of Surgical Pathology 38 (8): e50–9. Aug 2014. doi:10.1097/PAS.0000000000000233. PMID 24832161. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:SALL4&oldid=3551886"