Download Gene Section KLF5 (Kruppel-like factor 5 (intestinal)) Atlas of Genetics and Cytogenetics

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in Oncology and Haematology
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Gene Section
Review
KLF5 (Kruppel-like factor 5 (intestinal))
Ceshi Chen, Yinfa Zhou, Jin-Tang Dong
The Center for Cell Biology and Cancer Research Albany Medical College MS355/350, Mail code 165, 47
New Scotland Ave. Albany, NY 12208, USA
Published in Atlas Database: October 2006
Online updated version: http://AtlasGeneticsOncology.org/Genes/KLF5ID41074ch13q21.html
DOI: 10.4267/2042/38378
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
Transcription
Identity
About 3.4 Kb mRNA, 1374 bp open reading frame.
Hugo: KLF5
Other names: IKLF; BTEB2
Location: 13q21.3
Note: FISH study in PC-3 prostate cancer cell line
using BAC 505F3 as a probe.
Protein
Description
457 amino acids; about 55 kDa protein; KLF5 protein
undergoes numerous post translational modifications:
phosphorylation, acetylation, and ubiquitination. The
major transactivation domain is proline rich and
contains a PY motif (324-328), which can bind to E3
ubiquitin ligase WWP1. Three zinc finger domains at
C-terminus can bind to GC rich DNA sequence.
Expression
Widely expressed in intestine, prostate, breast, lung,
bladder, pancreas, placenta, uterus, skin, and skeletal
muscle.
Localisation
Nucleus.
Function
KLF5 is a transcription factor. Many KLF5 target
genes, such as PDGFa, PPARg, NFkB, cyclinD1,
KLF4, and TCR, have been identified in different cell
models. KLF5 regulates cell proliferation, cell cycle,
apoptosis, and differentiation. KLF5 is an important
transcription factor for cardiovascular remodeling and
tumor angiogenesis. KLF5 is essential for mouse
embryo development. Additionally, KLF5 may play an
important role in several tumor types including breast,
prostate, bladder, colon, esophagus, and skin.
DNA/RNA
Black box: Exon.
Description
Homology
KLF5 gene encompasses 4 exons which span about
18.7 kb of DNA. BAC clone RPCI-505F3 contains the
complete KLF5 genome sequence.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
KLF5 gene is highly-conserved among species (from
human to Drosophila). KLF5 belongs to the SP1/KLF
transcription factor family.
19
KLF5 (Kruppel-like factor 5 (intestinal))
Chen C et al.
TAD: transactivation domain, PY: PPPSY sequence.
found to be associated with shorter survival for breast
cancer patients. Using tissue microarray, we performed
immunohistochemical staining with the anti-KLF5 Ab.
The results suggest that KLF5 protein is generally weak
in normal breast epithelial cells but strongly positive in
breast tumors. Therefore, KLF5 expression is probably
a good prognosis marker for breast cancer.
Mutations
Somatic
The KLF5 gene is rarely mutated in human prostate
cancer. One point mutation (A → G), which change
Met294 to Val, has been found in the breast cancer cell
line MDA-MB-231.
Prostate cancer
Implicated in
Disease
The KLF5 gene is deleted in about 33% prostate cancer
cell lines/xenografts. Consistently, KLF5 mRNA is
down-regulated in these samples compared to three
immortalized prostate epithelial cell lines. In PC-3
prostate cancer cell line in which KLF5 mRNA is at
normal high level, KLF5 protein is excessively
degraded by over-expression of WWP1. KLF5 protein
is highly expressed in normal prostate epithelial cells
(see figure below). Forced expression of KLF5 inhibits
DU145 and 22Rv1 prostate cancer cell growth in vitro.
In contrast, KLF5 knock-down decreases RWPE1
immortalized prostate epithelial cell growth in vitro.
These results suggest that KLF5 may play a context
dependent role in prostate cancer.
Breast cancer
Disease
The KLF5 gene is deleted in about 43% breast cancer
cell lines. Consistently, KLF5 mRNA is downregulated in these cell lines. In 9 breast cancer cell lines
without KLF5 mRNA loss, KLF5 protein is excessively
degraded through ubiquitin-proteasome pathway.
Forced expression of KLF5 inhibits T-47D cancer cell
growth in vitro. In contrast, KLF5 expression is
upregulated in clinical breast tumor samples (see
below).
Prognosis
Recently, high level of KLF5 mRNA expression is
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
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KLF5 (Kruppel-like factor 5 (intestinal))
Chen C et al.
Bladder cancer
Esophagus cancer
Disease
KLF5 mRNA is down-regulated in several bladder
cancer cell lines. In TSu-Pr1 cell line, KLF5 overexpression promotes tumorigenesis in SCID mice.
Consistently, KLF5 promotes cell cycle progression
from G1 to S phase. Interestingly, KLF5 appears to
promote tumor angiogenesis. Microarray analysis
identified a number of angiogenic factors that are
potentially regulated by KLF5, including HBP17,
TGFa, and PDGFa. These findings suggest that the
KLF5 transcription factor may play an oncogenic role
in bladder cancer.
Disease
KLF5 is expressed in proliferating cells of the
gastrointestinal tract, including the esophagus.
Expression of KLF5 in a poorly differentiated
esophageal squamous cancer cell line TE2 inhibits
proliferation and invasion, decreases viability after
treatment with hydrogen peroxide and UV irradiation,
and increases anoikis. KLF5 upregulates the cdk
inhibitor p21 (waf1/cip1) and pro-apoptotic protein
BAX following UV irradiation.
Skin cancer
Disease
KLF5 is expressed predominantly in the basal layers of
the developing epidermis, in the basal layers of cells of
the inner root sheath, and in matrix cells of adult
human hair follicles. In a transgenic mouse model,
KLF5 over-expression in the basal layers of the
epidermis causes abnormal epidermal development and
differentiation. KLF5 over-expression may decrease the
proliferation of stem cell populations of bulge
keratinocytes.
Intestinal and colon cancer
Disease
Down-regulation of KLF5 may be an early event in
intestinal tumorigenesis. Expression of KLF5 in nontransformed intestinal epithelial cells enhances cell
growth; however, KLF5 inhibits cell growth in colon
cancer cell lines. Another group found that all-trans
retinoic acid inhibits intestinal epithelial cell growth in
vitro through inhibiting KLF5 expression. At the same
time,
lipopolysaccharide
(LPS)
induces
proinflammatory response in intestinal epithelial cells
through inducing KLF5 expression. These findings
suggest that KLF5 may play an important but yet to be
identified role in intestinal and colon cancer.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
Cardiovascular remodeling
Disease
KLF5 hemizygous knock-out mice reduce cardiac
hypertrophy and interstitial fibrosis upon infusion of
21
KLF5 (Kruppel-like factor 5 (intestinal))
Chen C et al.
Intestinal tumor progression is associated with altered function
of KLF5. J Biol Chem 2004;279:12093-12101.
angiotensin II. Additionally, KLF5 may play a role in
antherosclerosis and restenosis through regulating
vascular smooth muscle cells.
All-trans retinoic acid inhibits proliferation of intestinal epithelial
cells by inhibiting expression of the gene encoding Kruppel-like
factor 5. FEBS Lett 2004;578:99-105.
References
Human Kruppel-like factor 5 is a target of the E3 ubiquitin
ligase WWP1 for proteolysis in epithelial cells. J Biol Chem
2005;280:41553-41561.
A possible tumor suppressor role of the KLF5 transcription
factor in human breast cancer. Oncogene 2002;21:6567-6572.
Ubiquitin-proteasome degradation of KLF5 transcription factor
in cancer and untransformed epithelial cells. Oncogene
2005;24:3319-3327.
Opposing effects of Kruppel-like factor 4 (gut-enriched
Kruppel-like factor) and Kruppel-like factor 5 (intestinalenriched Kruppel-like factor) on the promoter of the Kruppellike factor 4 gene. Nucleic Acids Res 2002;30:2736-2741.
The deacetylase HDAC1 negatively regulates
the
cardiovascular transcription factor Kruppel-like factor 5 through
direct interaction. J Biol Chem 2005;280:12123-12129.
Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a
target for angiotensin II signaling and an essential regulator of
cardiovascular remodeling. Nat Med 2002;8:856-863.
Kruppel-like transcription factor KLF5 is a key regulator of
adipocyte differentiation. Cell Metab 2005;1:27-39.
Human Kruppel-like factor5/KLF5: synergy with NFkappaB/Rel factors and expression in human skin and hair
follicles. Eur J Cell Biol 2002;81:323-334.
KLF4 and KLF5 regulate proliferation, apoptosis and invasion
in esophageal cancer cells. Cancer Biol Ther 2005;4:12161221.
KLF5 is frequently deleted and down-regulated but rarely
mutated in prostate cancer. Prostate 2003;55:81-88.
Kruppel-like factor 5 is an important mediator for
lipopolysaccharide-induced proinflammatory response in
intestinal epithelial cells. Nucleic Acids Res 2006;34:12161223.
Positive and negative regulation of the cardiovascular
transcription factor KLF5 by p300 and the oncogenic regulator
SET through interaction and acetylation on the DNA-binding
domain. Mol Cell Biol 2003;23:8528-8541.
KLF5 promotes cell proliferation and tumorigenesis through
gene regulationin the TSU-Pr1 human bladder cancer cell line.
Int J Cancer 2006;118:1346-1355.
Downregulation and growth inhibitory effect of epithelial-type
Kruppel-like transcription factor KLF4, but not KLF5, in bladder
cancer. Biochem Biophys Res Commun 2003;308:251-256.
Epidermal and craniofacial defects in mice overexpressing Klf5
in the basal layer of the epidermis. J Cell Sci 2006;119:35933601.
Regulation of T-cell receptor D beta 1 promoter by KLF5
through reiterated GC-rich motifs. Blood 2003;101:4492-4499.
Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the
CBP interaction region enhances its transactivation function.
Nucleic Acids Res 2003;31:2196-2208.
This article should be referenced as such:
Chen C, Zhou Y, Dong JT. KLF5 (Kruppel-like factor 5
(intestinal)). Atlas Genet Cytogenet Oncol Haematol.2007;
11(1):19-22.
Regulation of platelet-derived growth factor-A chain by
Kruppel-like factor 5: new pathway of cooperative activation
with nuclear factor-kappaB. J Biol Chem 2004;279:70-76.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(1)
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