Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q9UID6 (Kruppel-like)
 147 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Kruppel-like transcription factor KLF6 is a novel tumor-suppressor gene mutated in a significant fraction of human prostate cancer. It is localized to human chromosome 10p14-15, a region that displays frequent loss of heterozygosity in glioblastoma multiforme (GBM). Indeed, mutations of the KLF6 gene have recently been reported in this tumor type. In this study, we report that the expression of KLF6 is attenuated in human GBM when compared with primary astrocytes. Expression of KLF6 in GBM cells reverts their tumorigenicity both in vitro and in vivo, which is correlated with its transactivation of the p21/CIP1/WAF1 promoter. Additionally, KLF6 inhibits cellular transformation induced by several oncogenes (c-sis/PDGF-B, v-src, H-Ras, and EGFR) that are components of signaling cascades implicated in GBM. Our results provide the first evidence of functional tumor suppression by KFL6, and its loss may contribute to glial tumor progression.
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PMID:Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. 1506 20

Kruppel-like factor 6 (KLF6/Zf9/CPBP), a member of the Kruppel-like family of zinc finger transcription factors, has recently been suggested to be a mutated tumor suppressor in selected human cancers. Initially, we investigated whether the KLF6 gene was altered in 36 paired non-small cell lung cancers (NSCLC), 89 brain tumors, 7 normal brains, 46 cancer cell lines from a large variety of tissues, and 144 peripheral blood cells from healthy individuals using single strand conformation polymorphism (PCR-SSCP) and DNA sequencing. Changes in the coding region of KLF6 were found in brain tumors (missense changes, 8%; silent polymorphisms, 2%), lung cancers (missense changes, 3%; silent polymorphisms, 6%) and cancer cell lines (missense changes, 2%; silent polymorphisms, 2%). All of the nucleotide changes in the lung tumor samples were present in their matched normal samples, suggesting that these changes were germline polymorphism. Many of the altered KLF6 genes found in the brain tumors were cloned into an expression vector and placed into a GBM cell line, and cell growth was monitored. Wild-type, deleted exon 3, or E30G missense KLF6 significantly reduced cell growth; in contrast, forced expression of KLF6 having either the S92R, P183L or A276G missense substitution did not alter the growth of transfected GBM cells (p > 0.05). Expression levels of KLF6 were higher in normal brain samples than in glioma samples as measured by real-time RT-PCR (p < 0.05). To our surprise, nucleotide changes were found at -4, -5, and -6 upstream of the start of translation in 45% of brain tumors, and 10% of normal blood samples. Focusing on the most frequent alteration (-4 C > A), the nucleotide change did not affect translation of KLF6. Taking together, KLF6 coding sequences are altered in 10% brain tumors, 8% NSLC, and 4% of cancer cell lines. All of those observed in lung cancer are germline polymorphisms. Several additional ones identified in GBM, have lost their ability to slow the growth of glioma cells; furthermore, a proportion of GBM have decreased expression of KLF6 as compared to normal brain tissue. Dysfunction of this gene may contribute to oncogenesis in the brain.
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PMID:KLF6: mutational analysis and effect on cancer cell proliferation. 1714 13

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor and possesses a high incidence of 10p loss. The KLF6 (Kruppel-like transcription factor) tumor suppressor gene on 10p15 is inactivated by loss of heterozygosity (LOH) and/or somatic mutation in a number of human cancers and forced expression of KLF6 in GBM lines inhibits their growth and transformation. In addition, increased expression of its alternatively spliced, cytoplasmic isoform KLF6-SV1 has now been shown to play a role in cancer pathogenesis. On the basis of these findings we examined the role of KLF6 and KLF6-SV1 in the development and progression of GBM. LOH analysis of 17 primary GBM patient samples using KLF6-specific microsatellite markers revealed that 88.2% (15/17) had LOH of the KLF6 locus. Interestingly, no KLF6 somatic mutations were identified. RNA analysis revealed concomitant decreases in all primary GBM tumors (n = 11) by approximately 80% in KLF6 expression (p < 0.001) coupled with increased KLF6-SV1 expression (p < 0.001) when compared to normal astrocytes. To determine the biological relevance of these findings, we examined the effect of KLF6 expression and KLF6-SV1 knockdown in A235 and CRL2020 cell lines. Reconstitution of KLF6 decreased cell proliferation by almost 50%, whereas targeted KLF6 reduction increased cell proliferation 2.5-4.5 fold. Conversely, targeted KLF6-SV1 reduction decreased cell proliferation by 50%. Taken together, our findings demonstrate that KLF6 allelic imbalance and decreased KLF6 and increased KLF6-SV1 expression are common findings in primary GBM tumors, and these changes have antagonistic effects on the regulation of cellular proliferation in GBM cell lines.
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PMID:Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblastoma. 1751 51