Disease relevance of KLF5

• However, in contrast to these effects in non-transformed cells, KLF5 reduced colony number, failed to enhance cyclin D1 transcription, and was negatively correlated with cell growth in colon cancer cell lines [1].
• Reduced levels of KLF5 mRNA were also detected in APC(min) mouse and human familial adenomatous polyposis adenomas compared with normal crypt epithelium, indicating that down-regulation of KLF5 is an early event in intestinal tumorigenesis in vivo [1].
• Re-expression of wild-type KLF5 in T-47D breast cancer cells significantly inhibited colony formation in these cells [2].
• KLF5 is frequently deleted and down-regulated but rarely mutated in prostate cancer [3].
• These results indicate that KLF5/BTEB2 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis [4].
• We show that LPA stimulated the expression levels of KLF5 mRNA and protein in colon cancer cells and this stimulation was mediated by LPA(2) and LPA(3) [5].

High impact information on KLF5

• Also, angiotensin II induced expression of KLF5, which in turn activated platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta (TGF-beta) expression [6].
• Krüppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling [6].
• In response to external stress, Klf5(+/-) mice showed diminished levels of arterial-wall thickening, angiogenesis, cardiac hypertrophy and interstitial fibrosis [6].
• SET negatively regulated KLF5 DNA binding, transactivation, and cell-proliferative activities [7].
• Down-regulation of the negative regulator SET was seen in response to KLF5-mediated gene activation [7].

Chemical compound and disease context of KLF5

• We also found that RARa binds KLF5/BTEB2, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy [4].

Biological context of KLF5

• A PY motif in a transactivation domain of KLF5 is necessary for its interaction with WWP1 [8].
• RNA interference analysis confirmed that KLF5 and p50 are important for induction of PDGF-A chain [9].
• The transduction of KLF4, but not KLF5, suppressed cell growth and induced apoptosis [10].
• Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer [10].
• However, phosphorylation is important in KLF5 transactivation activity [11].

Anatomical context of KLF5

• Finally, WWP1 was amplified and overexpressed in some cancer cell lines from the prostate and breast, which negatively regulated the function of KLF5 in gene regulation [8].
• In epithelial cells, the KLF5 protein is tightly regulated by the ubiquitin-proteasome pathway [8].
• Both genes were highly expressed in the normal bladder epithelium, whereas KLF4, but not KLF5, was frequently downregulated in bladder cancer cell lines and cancer tissues [10].
• The KLF5 mRNA and the protein is expressed in keratinocytes and throughout the adult human epidermis [12].
• Although both genes are expressed in the intestinal epithelium, their distributions are different: Klf4 is primarily expressed in the terminally differentiated villus cells while Klf5 is primarily in the proliferating crypt cells [13].

Associations of KLF5 with chemical compounds

• Furthermore, WWP1 mediated the ubiquitination and degradation of KLF5, and the catalytic cysteine residue of WWP1 is essential for its function [8].
• Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities [11].
• The KLF5 small interfering RNA-mediated down-regulation of survivin sensitized EU-4 cells to apoptosis induced by chemotherapeutic drug doxorubicin [14].
• RESULTS: Stimulation of VSMC with Ang II and TNF-alpha led to a rapid upregulation of KLF5 expression, and a later increase in SVV, which was cell-cycle independent [15].
• The AT(1) antagonist losartan significantly blocked Ang II-induced KLF5 expression [16].

Physical interactions of KLF5

• We found that WWP1 formed a protein complex with KLF5 in vivo and in vitro [8].
• KLF5 interacts with HDAC1 in the cell and in vitro [17].
• Chromatin immunoprecipitation assay showed KLF5/BTEB2 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation [4].
• Here, we report that KLF5 interacts with tumor suppressor p53 in regulating the expression of the inhibitor-of-apoptosis protein survivin, which may play a role in pathological process of cancer [14].
• BTEB2 is a GC box-binding transcription factor containing proline-rich and zinc finger domains as transactivation and DNA binding domains, respectively [18].

Regulatory relationships of KLF5

• Reporter assay also revealed that HDAC1 suppresses KLF5-dependent promoter activation [17].
• We demonstrated that the transactivation function of KLF5 was enhanced by CREB-binding protein (CBP) and blocked by wild-type but not mutant E1A [11].
• Thus KLF4 may preferentially activate DNA repair pathways while KLF5 induces both DNA repair and apoptosis after UV irradiation [19].
• BTEB2 mRNA expression is rapidly and persistently induced in SMCs by phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor [20].
• These results indicate that BTEB2 is a target of the early-response gene Egr-1, and mitogen-activated protein kinase pathways directly or indirectly activate BTEB2 expression [20].

Other interactions of KLF5

• Gel shift DNA binding assay showed that their interaction inhibits the DNA binding activity of KLF5, suggesting a property of HDAC1 to directly affect the DNA binding affinity of a transcription factor [17].
• Therefore, in this report we studied the involvement of the KLF4 and KLF5 genes in bladder carcinogenesis [10].
• Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function [11].
• Regulation of platelet-derived growth factor-A chain by Krüppel-like factor 5: new pathway of cooperative activation with nuclear factor-kappaB [9].
• Thus far PTEN is the most frequently mutated gene in prostate cancer, and KLF5 showed the most frequent hemizygous deletion and loss of expression [21].

Analytical, diagnostic and therapeutic context of KLF5

• First, we analyzed the expression of KLF4 and KLF5 in a variety of human bladder cancer cell lines and surgical specimens by RNA blot and in situ hybridization analyses [10].
• Using the real time TaqMan PCR assay, hemizygous deletion at KLF5 was detected in 13 out of 30, or 43% of breast cancer cell lines tested, and various degrees of loss of expression were detected in 21 out of 30, or 70% of these cell lines [2].
• Quantitative deletion of KLF5 genome occurred in six of the 18 (33%) prostate cancer xenografts/cell lines [3].
• Deletion and mutation analyses as well as chromatin immunoprecipitation and electronic mobility shift assay indicated that KLF5 binds to the core survivin promoter and strongly induces its activity [14].
• Expression of KLF5 is a prognostic factor for disease-free survival and overall survival in patients with breast cancer [22].

References