Download Gene Section LOXL4 (lysyl oxidase-like 4) Atlas of Genetics and Cytogenetics

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in Oncology and Haematology
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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