Alternative titles; symbols
HGNC Approved Gene Symbol:KLF6
Cytogenetic location:10p15.2 Genomic coordinates(GRCh38) :10:3,775,996-3,785,209 (from NCBI)
KLF6 is a member of the Kruppel-like transcription factor family (Ratziu et al., 1998).
Members of the pregnancy-specific glycoprotein (PSG) family and related genes do not have TATA boxes or the initiator in their promoter regions. To identify proteins that regulate PSG gene expression,Koritschoner et al. (1997) screened a placenta expression library with the core promoter element (CPE) from PSG5 (176394). They isolated cDNAs encoding a protein that they called 'core promoter element-binding protein' (CBPB or COPEB). By sequence analysis,Koritschoner et al. (1997) found 2 possible translation initiation codons, use of which would produce predicted proteins of either 283 or 290 amino acids. COPEB contains an N-terminal acidic domain, a serine/threonine-rich central region, and 3 contiguous zinc finger domains in the C-terminal region. The in vitro COPEB translation product had a mass of 32 kD by SDS-PAGE. Using mammalian cells expressing COPEB,Koritschoner et al. (1997) showed that COPEB is capable of activating transcription approximately 4-fold from the PSG5 promoter. A Gal4-COPEB fusion protein activated transcription from a heterologous promoter containing Gal4 binding sites. Northern blot analysis revealed that COPEB is expressed as a 4.5-kb mRNA in several tissues, with the highest levels in placenta.
El Rouby and Newcomb (1996) identified a novel protooncogene expressed in B cells, designated BCD1 by them. They cloned it from the peripheral blood lymphocytes of a B-cell chronic lymphocytic leukemia patient through its capacity to transform NIH 3T3 cells. The expression of the BCD1 gene was limited to 2 tissues, CD19+ B-cells and testis of normal individuals. Malignant B cells from 50% of patients with B-cell chronic lymphocytic leukemia studied showed no detectable BCD1 gene transcripts; however, when malignant B cells were stimulated to undergo terminal differentiation into plasma cells, BCD1 gene expression was induced, suggesting an association with B-cell maturation. Since the BCD1 sequence was isolated from a leukemia patient,Patrito and Bocco (1998) suggested that the sequence differences between COPEB and BCD1 arose as a consequence of tumor development. The differences may be due to a rearrangement between COPEB and another ubiquitously expressed protein, resulting in a fusion protein, or to multiple mutations in COPEB.
Wound repair in parenchymal tissues requires coordinate changes in resident mesenchymal cells that ultimately lead to fibrosis. In the liver, this response involves hepatic stellate cells, which are a nonparenchymal cell type located in the subendothelial space of the sinusoid. Stellate cells express the myogenic intermediate filament desmin, and, in normal liver, are the primary storage site for retinoids, which are found in cytoplasmic droplets in retinyl esters. Analogous cells in other organs include mesangial cells in kidney and pulmonary fibroblasts in lung. The response of stellate cells to injury is termed 'activation' and represents a cellular program with a distinct temporal sequence involving both up- and downregulation of gene expression. The methods for isolating and culturing stellate cells are useful for exploring molecular mechanisms of stellate cell activation. To broaden the search for transcription factors involved in the activation process, subtraction hybridization was used to identify transcripts induced early in rat stellate cells in vivo after a single dose of carbon tetrachloride (CCl4), a known precipitant of hepatic fibrosis. In this way cDNA showing homology to zinc finger proteins was isolated.Ratziu et al. (1998) isolated full-length rat and human cDNAs, which they termed ZF9, and characterized production of ZF9 protein. They established that ZF9 is a nuclear DNA-binding protein in activated cells that, in a context-dependent manner, transactivates a key promoter driving stellate cell fibrogenesis. The ZF9 nucleotide sequence predicts that it is a member of the Kruppel-like family with a unique N-terminal domain rich in serine-proline clusters and leucines. ZF9 binds specifically to a DNA oligonucleotide containing a GC-box motif.Ratziu et al. (1998) noted that COPEB/BCD1 is the human homolog of Zf9.
El Rouby et al. (1997) determined the chromosomal assignment of BCD1 by Southern blot analysis of human/rodent somatic cell hybrids that contain a single chromosome or several different human chromosomes in one or more hybrid cell lines. The assignment to chromosome 10 was confirmed and refined by fluorescence in situ hybridization (FISH), which localized the gene to 10p15-p14. By FISH,Onyango et al. (1998) further refined the map position to 10p15. By the same method,Ratziu et al. (1998) assigned the ZF9 gene to 10p.
Narla et al. (2001) demonstrated that KLF6 is mutated in a subset of human prostate cancer. Loss of heterozygosity analysis revealed that 1 KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirmed that whereas wildtype KLF6 upregulates p21 (WAF1/CIP1;116899) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Furthermore,Narla et al. (2001) demonstrated that separate malignant foci within prostate cancers from the same patient contained different KLF6 mutations.Narla et al. (2001) observed that 18 of 33 prostate tumors had KLF6 mutations. Of the 26 mutations identified, 23 were within the KLF6 transactivation domain. These mutations resulted in 25 nonconservative amino acid changes and the introduction of a premature stop codon. None of these mutations was present in the patient's normal prostate tissue DNA or in germline DNA from 100 chromosomes of 50 unaffected, unrelated individuals. The majority of the mutations affected highly conserved amino acids, suggesting that these residues are functionally important.
In a set of 80 sporadic gastric cancers,Cho et al. (2005) identified 4 missense mutations in exon 2 of the KLF6 gene (see, e.g.,602053.0006); the mutations were absent from corresponding normal tissue, suggesting somatic mutation. In addition, 16 (43.2%) of 37 informative cases showed allelic loss at the KLF6 locus. All of the cases with mutation and 13 of the 16 with allelic loss were of advanced intestinal-type gastric cancer with lymph node metastasis.
In the tumor of a patient with prostate cancer (176807),Narla et al. (2001) identified loss of heterozygosity for 1 KLF6 allele and a T-to-C transition resulting in a serine-to-proline substitution at amino acid 116 (S116P).
In the tumor of a patient with prostate cancer (176807),Narla et al. (2001) found loss of heterozygosity for the KLF6 gene on 1 allele and a C-to-A transversion resulting in a serine-to-termination codon substitution at residue 137 (S137X).
In the tumor of a patient with prostate cancer (176807),Narla et al. (2001) identified a C-to-A transversion resulting in an alanine-to-aspartic acid substitution at residue 123 (A123D) in the tumor as well as loss of heterozygosity for the wildtype KLF6 allele. These mutations were not identified in the germline.
In the tumor of a patient with prostate cancer (176807),Narla et al. (2001) identified a C-to-T transition in the KLF6 gene resulting in a tryptophan-to-arginine substitution at residue 64 (W64R). The tumor had deletion of the other KLF6 allele.
In a tumor of a patient with prostate cancer (176807),Narla et al. (2001) identified a T-to-C transition in the KLF6 gene resulting in a leucine-to-proline substitution at residue 169 (L169P). The tumor also had loss of the other KLF6 allele.
In tumor tissue from a sporadic gastric cancer of the intestinal type (137215),Cho et al. (2005) identified heterozygosity for a 3412C-A transversion in exon 2 of the KLF6 gene, resulting in a ser155-to-arg (S155R) substitution in the transactivation domain. The mutation was not found in corresponding normal tissue, suggestive of somatic mutation.
Cho, Y. G., Kim, C. J., Park, C. H., Yang, Y. M., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., Park, W. S.Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 24: 4588-4590, 2005. [PubMed:15824733,related citations] [Full Text]
El Rouby, S., Newcomb, E. W.Identification of Bcd, a novel proto-oncogene expressed in B-cells. Oncogene 13: 2623-2630, 1996. [PubMed:9000136,related citations]
El Rouby, S., Rao, P. H., Newcomb, E. W.Assignment of the human B-cell-derived (BCD1) proto-oncogene to 10p14-p15. Genomics 43: 395-397, 1997. [PubMed:9268646,related citations] [Full Text]
Koritschoner, N. P., Bocco, J. L., Panzetta-Dutari, G. M., Dumur, C. I., Flury, A., Patrito, L. C.A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J. Biol. Chem. 272: 9573-9580, 1997. [PubMed:9083102,related citations] [Full Text]
Narla, G., Heath, K. E., Reeves, H. L., Li, D., Giono, L. E., Kimmelman, A. C., Glucksman, M. J., Narla, J., Eng, F. J., Chan, A. M., Ferrari, A. C., Martignetti, J. A., Friedman, S. L.KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294: 2563-2566, 2001. [PubMed:11752579,related citations] [Full Text]
Onyango, P., Koritschoner, N. P., Patrito, L. C., Zenke, M., Weith, A.Assignment of the gene encoding the core promoter element binding protein (COPEB) to human chromosome 10p15 by somatic hybrid analysis and fluorescence in situ hybridization. Genomics 48: 143-144, 1998. [PubMed:9503030,related citations] [Full Text]
Patrito, L. C., Bocco, J. L.Personal Communication. Cordoba, Argentina 6/17/1998.
Ratziu, V., Lalazar, A., Wong, L., Dang, Q., Collins, C., Shaulian, E., Jensen, S., Friedman, S. L.Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc. Nat. Acad. Sci. 95: 9500-9505, 1998. [PubMed:9689109,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: KLF6
Cytogenetic location: 10p15.2 Genomic coordinates(GRCh38) : 10:3,775,996-3,785,209(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 10p15.2 | Gastric cancer, somatic | 613659 | 3 | |
| Prostate cancer, somatic | 176807 | 3 |
KLF6 is a member of the Kruppel-like transcription factor family (Ratziu et al., 1998).
Members of the pregnancy-specific glycoprotein (PSG) family and related genes do not have TATA boxes or the initiator in their promoter regions. To identify proteins that regulate PSG gene expression, Koritschoner et al. (1997) screened a placenta expression library with the core promoter element (CPE) from PSG5 (176394). They isolated cDNAs encoding a protein that they called 'core promoter element-binding protein' (CBPB or COPEB). By sequence analysis, Koritschoner et al. (1997) found 2 possible translation initiation codons, use of which would produce predicted proteins of either 283 or 290 amino acids. COPEB contains an N-terminal acidic domain, a serine/threonine-rich central region, and 3 contiguous zinc finger domains in the C-terminal region. The in vitro COPEB translation product had a mass of 32 kD by SDS-PAGE. Using mammalian cells expressing COPEB, Koritschoner et al. (1997) showed that COPEB is capable of activating transcription approximately 4-fold from the PSG5 promoter. A Gal4-COPEB fusion protein activated transcription from a heterologous promoter containing Gal4 binding sites. Northern blot analysis revealed that COPEB is expressed as a 4.5-kb mRNA in several tissues, with the highest levels in placenta.
El Rouby and Newcomb (1996) identified a novel protooncogene expressed in B cells, designated BCD1 by them. They cloned it from the peripheral blood lymphocytes of a B-cell chronic lymphocytic leukemia patient through its capacity to transform NIH 3T3 cells. The expression of the BCD1 gene was limited to 2 tissues, CD19+ B-cells and testis of normal individuals. Malignant B cells from 50% of patients with B-cell chronic lymphocytic leukemia studied showed no detectable BCD1 gene transcripts; however, when malignant B cells were stimulated to undergo terminal differentiation into plasma cells, BCD1 gene expression was induced, suggesting an association with B-cell maturation. Since the BCD1 sequence was isolated from a leukemia patient, Patrito and Bocco (1998) suggested that the sequence differences between COPEB and BCD1 arose as a consequence of tumor development. The differences may be due to a rearrangement between COPEB and another ubiquitously expressed protein, resulting in a fusion protein, or to multiple mutations in COPEB.
Wound repair in parenchymal tissues requires coordinate changes in resident mesenchymal cells that ultimately lead to fibrosis. In the liver, this response involves hepatic stellate cells, which are a nonparenchymal cell type located in the subendothelial space of the sinusoid. Stellate cells express the myogenic intermediate filament desmin, and, in normal liver, are the primary storage site for retinoids, which are found in cytoplasmic droplets in retinyl esters. Analogous cells in other organs include mesangial cells in kidney and pulmonary fibroblasts in lung. The response of stellate cells to injury is termed 'activation' and represents a cellular program with a distinct temporal sequence involving both up- and downregulation of gene expression. The methods for isolating and culturing stellate cells are useful for exploring molecular mechanisms of stellate cell activation. To broaden the search for transcription factors involved in the activation process, subtraction hybridization was used to identify transcripts induced early in rat stellate cells in vivo after a single dose of carbon tetrachloride (CCl4), a known precipitant of hepatic fibrosis. In this way cDNA showing homology to zinc finger proteins was isolated. Ratziu et al. (1998) isolated full-length rat and human cDNAs, which they termed ZF9, and characterized production of ZF9 protein. They established that ZF9 is a nuclear DNA-binding protein in activated cells that, in a context-dependent manner, transactivates a key promoter driving stellate cell fibrogenesis. The ZF9 nucleotide sequence predicts that it is a member of the Kruppel-like family with a unique N-terminal domain rich in serine-proline clusters and leucines. ZF9 binds specifically to a DNA oligonucleotide containing a GC-box motif. Ratziu et al. (1998) noted that COPEB/BCD1 is the human homolog of Zf9.
El Rouby et al. (1997) determined the chromosomal assignment of BCD1 by Southern blot analysis of human/rodent somatic cell hybrids that contain a single chromosome or several different human chromosomes in one or more hybrid cell lines. The assignment to chromosome 10 was confirmed and refined by fluorescence in situ hybridization (FISH), which localized the gene to 10p15-p14. By FISH, Onyango et al. (1998) further refined the map position to 10p15. By the same method, Ratziu et al. (1998) assigned the ZF9 gene to 10p.
Narla et al. (2001) demonstrated that KLF6 is mutated in a subset of human prostate cancer. Loss of heterozygosity analysis revealed that 1 KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirmed that whereas wildtype KLF6 upregulates p21 (WAF1/CIP1; 116899) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Furthermore, Narla et al. (2001) demonstrated that separate malignant foci within prostate cancers from the same patient contained different KLF6 mutations. Narla et al. (2001) observed that 18 of 33 prostate tumors had KLF6 mutations. Of the 26 mutations identified, 23 were within the KLF6 transactivation domain. These mutations resulted in 25 nonconservative amino acid changes and the introduction of a premature stop codon. None of these mutations was present in the patient's normal prostate tissue DNA or in germline DNA from 100 chromosomes of 50 unaffected, unrelated individuals. The majority of the mutations affected highly conserved amino acids, suggesting that these residues are functionally important.
In a set of 80 sporadic gastric cancers, Cho et al. (2005) identified 4 missense mutations in exon 2 of the KLF6 gene (see, e.g., 602053.0006); the mutations were absent from corresponding normal tissue, suggesting somatic mutation. In addition, 16 (43.2%) of 37 informative cases showed allelic loss at the KLF6 locus. All of the cases with mutation and 13 of the 16 with allelic loss were of advanced intestinal-type gastric cancer with lymph node metastasis.
In the tumor of a patient with prostate cancer (176807), Narla et al. (2001) identified loss of heterozygosity for 1 KLF6 allele and a T-to-C transition resulting in a serine-to-proline substitution at amino acid 116 (S116P).
In the tumor of a patient with prostate cancer (176807), Narla et al. (2001) found loss of heterozygosity for the KLF6 gene on 1 allele and a C-to-A transversion resulting in a serine-to-termination codon substitution at residue 137 (S137X).
In the tumor of a patient with prostate cancer (176807), Narla et al. (2001) identified a C-to-A transversion resulting in an alanine-to-aspartic acid substitution at residue 123 (A123D) in the tumor as well as loss of heterozygosity for the wildtype KLF6 allele. These mutations were not identified in the germline.
In the tumor of a patient with prostate cancer (176807), Narla et al. (2001) identified a C-to-T transition in the KLF6 gene resulting in a tryptophan-to-arginine substitution at residue 64 (W64R). The tumor had deletion of the other KLF6 allele.
In a tumor of a patient with prostate cancer (176807), Narla et al. (2001) identified a T-to-C transition in the KLF6 gene resulting in a leucine-to-proline substitution at residue 169 (L169P). The tumor also had loss of the other KLF6 allele.
In tumor tissue from a sporadic gastric cancer of the intestinal type (137215), Cho et al. (2005) identified heterozygosity for a 3412C-A transversion in exon 2 of the KLF6 gene, resulting in a ser155-to-arg (S155R) substitution in the transactivation domain. The mutation was not found in corresponding normal tissue, suggestive of somatic mutation.
Cho, Y. G., Kim, C. J., Park, C. H., Yang, Y. M., Kim, S. Y., Nam, S. W., Lee, S. H., Yoo, N. J., Lee, J. Y., Park, W. S.Genetic alterations of the KLF6 gene in gastric cancer. Oncogene 24: 4588-4590, 2005. [PubMed: 15824733] [Full Text: https://doi.org/10.1038/sj.onc.1208670]
El Rouby, S., Newcomb, E. W.Identification of Bcd, a novel proto-oncogene expressed in B-cells. Oncogene 13: 2623-2630, 1996. [PubMed: 9000136]
El Rouby, S., Rao, P. H., Newcomb, E. W.Assignment of the human B-cell-derived (BCD1) proto-oncogene to 10p14-p15. Genomics 43: 395-397, 1997. [PubMed: 9268646] [Full Text: https://doi.org/10.1006/geno.1997.4824]
Koritschoner, N. P., Bocco, J. L., Panzetta-Dutari, G. M., Dumur, C. I., Flury, A., Patrito, L. C.A novel human zinc finger protein that interacts with the core promoter element of a TATA box-less gene. J. Biol. Chem. 272: 9573-9580, 1997. [PubMed: 9083102] [Full Text: https://doi.org/10.1074/jbc.272.14.9573]
Narla, G., Heath, K. E., Reeves, H. L., Li, D., Giono, L. E., Kimmelman, A. C., Glucksman, M. J., Narla, J., Eng, F. J., Chan, A. M., Ferrari, A. C., Martignetti, J. A., Friedman, S. L.KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294: 2563-2566, 2001. [PubMed: 11752579] [Full Text: https://doi.org/10.1126/science.1066326]
Onyango, P., Koritschoner, N. P., Patrito, L. C., Zenke, M., Weith, A.Assignment of the gene encoding the core promoter element binding protein (COPEB) to human chromosome 10p15 by somatic hybrid analysis and fluorescence in situ hybridization. Genomics 48: 143-144, 1998. [PubMed: 9503030] [Full Text: https://doi.org/10.1006/geno.1997.5124]
Patrito, L. C., Bocco, J. L.Personal Communication. Cordoba, Argentina 6/17/1998.
Ratziu, V., Lalazar, A., Wong, L., Dang, Q., Collins, C., Shaulian, E., Jensen, S., Friedman, S. L.Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc. Nat. Acad. Sci. 95: 9500-9505, 1998. [PubMed: 9689109] [Full Text: https://doi.org/10.1073/pnas.95.16.9500]
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