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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review LOXL4 (lysyl oxidase-like 4) Kornelia Molnarne Szauter, Tibor Görögh, Katalin Csiszar Division of Experimental Oncology, Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Germany (TG); John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA (KMS, KC) Published in Atlas Database: April 2007 Online updated version: http://AtlasGeneticsOncology.org/Genes/LOXL4ID41193ch10q24.html DOI: 10.4267/2042/15938 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology (TGA) is at position 14.480. In the 3’UTR there is a 1230 bp untranslated trailer sequence and two consensus polyadenylation signals have been located 30 bp and 322 upstream of the poly-A tail. Identity Hugo: LOXL4 Other names: LOXC (mouse); EER-7 (endothelial estrogen-regulated gene-7) Location: 10q24.2 Protein Note: Western blot analysis of HT-1080 cells detected the recombinant and secreted LOXL4 form as slightly larger than the cellular 85 kDa form probably due to glycosylation or other modifications, some of which may be cell type dependent. DNA/RNA Note: LOXL4 (lysyl oxidase-like 4) is a member of the lysyl oxidase (LOX) family. Its C-terminal region is conserved in all five members of this copper-dependent amine oxidase family and includes a copper-binding site, lysyl and tyrosine residues that form the lysyltyrosine-quinone cofactor (LTQ) and a cytokine receptor-like domain. The N-terminal region of LOXL4 contains four scavenger receptor cysteine-rich (SRCR) domains and has homology with LOXL2 and LOXL3, but not with LOX or LOXL that do not contain these domains. The second SRCR domain contains a 13 amino acid insertion that is unique to LOXL4. Description The predicted LOXL4 protein is 756 amino acids including a 24 amino acid signal peptide, with a molecular mass of approximately 84.5 kDa. Expression In tissues the LOXL4 mRNA is expressed in the placenta, trachea, lung, kidney, pancreas, testis, aorta liver, fetal liver and at lover levels in several other tissues that include the heart, skeletal muscle, spleen, prostate, ovary, small intestine, colon, bladder, and thyroid, adrenal, salivary and mammary glands. LOXL4 mRNA was also reported in vocal cord, laryngeal, hypopharyngeal, parotid and oropharyngeal carcinoma tumor biopsies. The LOXL4 mRNA was reported in cultured fibroblasts, smooth muscle cells, MDA-MB-231 breast cancer and osteosarcoma (OHS) cells. Both mRNA and immunohistochemistry analyses demonstrated LOXL4 expression in head and neck squamous cell carcinoma (HNSSC) tissues and cultured cell lines. No mRNA expression was detected in HCT116 and DLD-1 colon, MCF7, T47D and Hs578T breast and DU-145 prostate cancer lines. The mouse homologue of LOXL4, reported as LOXC, was identified as a mRNA expressed in calcified ATDC5 cells, MC3T3-E1 cells, C3H10T1/2 embryonic Description The LOXL4 genomic sequence is 14.095 kb with an open reading frame of 2.278 kb and a 5’UTR of 384 bases. The TATA-box is at -25 and the TRE sequence, TGACTCA (TPA-responsive element), is at -75. The GATA domain is located at -113 and -669, and the RFX1 transactivator binding site, GGAA, is found at 149. Sp1 transcription factor consensus sequence, GGCGGC, is at -181, CCAAT (CP1-factor) at -257 and -892 and the repetitive sequence motif GAAA at -310 and 329. No GC box is present in the promoter region. Transcription The 14 exons of the LOXL4 gene make up an mRNA of 3.877 kb with a coding region of 2.278 kb. Transcriptional start site is at +384 upstream of the translation initiation codon (ATG). The first stop codon Atlas Genet Cytogenet Oncol Haematol. 2007;11(4) 274 LOXL4 (lysyl oxidase-like 4) Szauter KM et al. nose synus, primary and metastatic tumors of the larynx, hypopharynx and tongue and metastatic tumor of the thyroid gland and in 90% of primary or metastatic HNSSC cell lines. Disease Invasive head and neck carcinoma. Prognosis Significant correlation was found between LOXL4 expression and regional lymph node metastases and strong LOXL4 expression was present in metastatic HNSCC cell lines. There is no information regarding LOXL4 expression in distant metastases as patients with distant metastases are predominantly treated not surgically, but with radio- and/or chemotherapy. Cytogenetics Isochromosome i(10)(q10) was found associated with an amplification of the LOXL4 gene locus at 10q24 in a subset of interphase nuclei in UTSCC19A and HLAC78 head and neck carcinoma cells. fibroblast and myoblastic C2C12 cells. Up-regulation of the LOXL4 mRNA (EER-7) was reported 100-fold in human umbilical vein endothelial cells (HUVECs) transfected with estrogen receptor (alpha and beta) in response to treatment with 17beta-estrogen. Localisation The recombinant LOXL4 protein in human HT-1080 fibrosarcoma cell line localized both intra- and extracellularly. In HNSCC, LOXL4 immunohistochemical staining was prevalently cytoplasmic in poorly differentiated cases with increasing perinuclear staining in well-differentiated areas. In HTB-43 pharyngeal SCC cells LOXL4 staining revealed a punctate pattern within cells with perinuclear enrichment. This pattern suggested containment of LOXL4 in the endomembrane sytem of cells at sites of synthesis and vesicular transport for secretion at the cell surface. Flow cytometry (FACS) analysis demonstrated that approximately 15% of these cells had LOXL4 localized on their surface. In contrast, LOXL4 expression was not detected (or only to a very low extent) in cultured normal epithelial cells derived from oral mucosa samples. References Asuncion L, Fogelgren B, Fong KS, Fong SF, Kim Y, Csiszar K. A novel human lysyl oxidase-like gene (LOXL4) on chromosome 10q24 has an altered scavenger receptor cysteine rich domain. Matrix Biol 2001;20(7):487-491. Function LOXL4 may function as an active amine oxidase, as betaAPN (beta-aminopropionitrile) inhibitable enzymatically active recombinant human LOXL4 was generated in an E. coli expression system and positively evaluated for its catalytic activity with a diamine substrate. The mouse homologue of LOXL4, LOXC, showed similar betaAPN inhibitable catalytic activity when tested using a collagen substrate. Ito H, Akiyama H, Iguchi H, Iyama K, Miyamoto M, Ohsawa K, Nakamura T. Molecular cloning and biological activity of a novel lysyl oxidase-related gene expressed in cartilage. J Biol Chem 2001;276(26):24023-24029. Mäki JM, Tikkanen H, Kivirikko KI. Cloning and characterization of a fifth human lysyl oxidase isoenzyme: the third member of the lysyl oxidase-related subfamily with four scavenger receptor cysteine-rich domains. Matrix Biol 2001;20(7):493-496. Homology Evans MJ, Harris HA, Miller CP, Karathanasis SK, Adelman SJ. Estrogen receptors alpha and beta have similar activities in multiple endothelial cell pathways. Endocrinology 2002;143(10):3785-3795. LOXL4 has homology with the C-terminal domains to LOX, LOXL1, LOXL2 and LOXL3 and homology with the four N-terminal SRCR domains of LOXL2 and LOXL3. Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ. A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res 2002;62(15):4478-4483. Implicated in Holtmeier C, Görögh T, Beier U, Meyer J, Hoffmann M, Gottschlich S, Heidorn K, Ambrosch P, Maune S. Overexpression of a novel lysyl oxidase-like gene in human head and neck squamous cell carcinomas. Anticancer Res 2003;23(3B):2585-2591. Breast cancer invasion Note: LOXL4 mRNA was expressed in MDA-MB-231 highly invasive breast cancer cells, but not in poorly invasive and non-metastatic breast cancer cells MCF7 and T47D. Disease Breast cancer. Kim MS, Kim SS, Jung ST, Park JY, Yoo HW, Ko J, Csiszar K, Choi SY, Kim Y. Expression and purification of enzymatically active forms of the human lysyl oxidase-like protein 4. J Biol Chem 2003;278(52):52071-52074. Görögh T, Weise J, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K. Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma. J Pathol 2007;[Epub ahead of print]. Human head and neck squamous cell carcinoma (HNSSC) Note: LOXL4 mRNA was detected in 16 HNSSC cell lines, obtained from recurrent and primary tumors, whereas no expression was detected in normal epithelial cells. LOXL4 was also found over-expressed in 71% of invasive HNSSC tumors and primary tumors of the glottic larynx, parotic gland, oropharynx and Atlas Genet Cytogenet Oncol Haematol. 2007;11(4) This article should be referenced as such: Szauter KM, Gorogh T, Csiszar K. LOXL4 (lysyl oxidase-like 4). Atlas Genet Cytogenet Oncol Haematol.2007;11(4):274275. 275