Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1

Benzeno, Sharon; Narla, Goutham; Allina, Jorge; Cheng, George Z.; Reeves, Helen L.; Banck, Michaela S.; Odin, Joseph A.; Diehl, J. Alan; Germain, Doris; Friedman, Scott L.

doi:10.1158/0008-5472.can-03-2818

Cited by 140 publications

(121 citation statements)

References 44 publications

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“…Overexpression of cyclins has also been observed frequently in HCC cases, 25 and we recently demonstrated that KLF6 can bind and inactivate cyclin D1 and converge with the Rb pathway. 26 KLF6 may also up-regulate the insulin-like growth factor 1 receptor, 27 the loss of which could contribute to HCC. 28 Finally, apoptotic activity of KLF6 has been reported in lung cancer cell lines, 13 and down-regulation of this apoptotic potential could enable emergence of neoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

et al. 2004

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Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Krüppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39% of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild-type KLF6 decreased cellular proliferation of HepG2 cells, while patient-derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors.

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Section: Discussionmentioning

confidence: 99%

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

et al. 2004

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“…cdk4 Immunoprecipitation Kinase Assay-This was performed essentially as described previously (22). Cells were lysed in 50 mM Hepes (pH 7.5), 150 mM NaCl, 1 mM EDTA, 0.1% Nonidet P-40 detergent with 10% glycerol, 100 M phenylmethylsulfonyl fluoride, 10 g/ml aprotinin, 10 g/ml leupeptin, 100 M sodium vanadate, and 20 g/ml TLCK (1 h, 4°C), centrifuged, and 700 g of lysate was immunoprecipitated with mAb anti-cdk4, mAb anti-cyclin D1, or mouse IgG (overnight, 4°C).…”

Section: Kip2mentioning

confidence: 99%

p27Kip1 and Cyclin D1 Are Necessary for Focal Adhesion Kinase Regulation of Cell Cycle Progression in Glioblastoma Cells Propagated in Vitro and in Vivo in the Scid Mouse Brain

Ding

Grammer

Nelson

et al. 2005

Journal of Biological Chemistry

116

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We have reported previously that the expression of focal adhesion kinase (FAK) is elevated in glioblastomas and that expression of FAK promotes the proliferation of glioblastoma cells propagated in either soft agar or in the C.B.17 severe combined immunodeficiency (scid) mouse brain. We therefore determined the effect of FAK on cell cycle progression in these cells. We found that overexpression of wild-type FAK promoted exit from G 1 in monolayer cultures of glioblastoma cells, enhanced the expression of cyclins D1 and E while reducing the expression of p27 Kip1 and p21 Waf1 , and enhanced the kinase activity of the cyclin D1-cyclin-dependent kinase-4 (cdk4) complex. Transfection of the monolayers with a FAK molecule in which the autophosphorylation site is mutated (FAK397F) inhibited exit from G 1 and reduced the expression of cyclins D1 and E while enhancing the expression of p27 Kip1 and p21 Waf1 . Small interfering RNA (siRNA)-mediated down-regulation of cyclin D1 inhibited the enhancement of cell cycle progression observed on expression of wild-type FAK, whereas siRNA-mediated down-regulation of cyclin E had no effect. siRNAmediated down-regulation of p27Kip1 overcame the inhibition of cell cycle progression observed on expression of FAK397F, whereas down-regulation of p21Waf1 had no effect. These results were confirmed in vivo in the scid mouse brain xenograft model in which propagation of glioblastoma cells expressing FAK397F resulted in a 50% inhibition of tumor growth and inhibited exit from G 1 . Taken together, our results indicate that FAK promotes proliferation of glioblastoma cells by enhancing exit from G 1 through a mechanism that involves cyclin D1 and p27 Kip1 .FAK 1 is a nonreceptor cytoplasmic tyrosine kinase. It has been shown to be activated on clustering of integrin receptors in the cell membrane or by the ligation of multiple growth factor receptors (1-3). Activation occurs through phosphorylation of Tyr 397 , either through autophosphorylation or Src-induced phosphorylation (4). Clustering of integrin receptors occurs during cell attachment, and the receptors localize to focal contacts (early adhesion complexes) where, in a temporally related manner, a signaling complex is assembled which includes FAK as well as cellular Src and other kinases, cytoskeletal proteins, and adaptor molecules (3, 5, 6). In nonmalignant and nontransformed cells, this localization of FAK to focal contacts or focal adhesions (mature adhesion complexes) has been shown to be necessary for its activation, indicating that FAK activation is regulated by integrin receptor engagement or cell adhesion in these cells. In contrast, in malignant or transformed cells, the activation of FAK does not appear to be regulated solely by cell adhesion or integrin receptor engagement. For example, we have shown the activation of FAK (phosphorylation of Tyr 397 ) in glioblastoma cells propagated in suspension, suggesting that the mechanisms governing the activation of FAK in malignant or transformed cells may differ from those util...

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“…The Klf6 transcription factor acts to regulate transcription of Ccnd1 (Benzeno et al 2004). The Klf6 gene was suggested to be overexpressed in the PO × BW class.…”

Section: Perturbation Of Cell Cycle Regulatory Genes In the F 1 Hybridsmentioning

confidence: 99%

Changes in cell cycle and extracellular matrix gene expression during placental development in deer mouse (Peromyscus) hybrids

Duselis

Obergfell

Mack

et al. 2007

Reprod. Fertil. Dev.

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Abstract.Crosses between two species of the rodent genus Peromyscus produce defects in both growth and development. The defects are pronounced in the hybrid placentas. Peromyscuys maniculatus (strain BW) females mated to P. polionotus (strain PO) males produce placentas half the size of the parental species, as well as growth-retarded embryos. In contrast, PO females mated to BW males result in defective conceptuses that display embryonic and placental overgrowth. These 'parent-of-origin'-dependent phenotypes are consistent with previous studies that demonstrated altered expression of imprinted genes and genetic linkage of the overgrowth phenotypes to imprinted domains. In the present study, we take a broader approach in assessing perturbations in hybrid placental gene expression through the use of Mus musculus cDNA microarrays. In verifying classes of genes identified in microarray screens differentially regulated during hybrid placental development, we focused on those influencing the cell cycle and extracellular matrix (ECM). Our work suggests that cell cycle regulators at the G 1 /S phase check-point are downregulated in the large hybrid placenta, whereas the small hybrid placenta is more variable. The ECM genes are typically downstream targets of cell cycle regulation and their misregulation is consistent with many of the dysmorphic phenotypes. Thus, these data suggest imbalances in proliferation and differentiation in hybrid placentation.

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Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1

Cited by 140 publications

References 44 publications

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

p27Kip1 and Cyclin D1 Are Necessary for Focal Adhesion Kinase Regulation of Cell Cycle Progression in Glioblastoma Cells Propagated in Vitro and in Vivo in the Scid Mouse Brain

Changes in cell cycle and extracellular matrix gene expression during placental development in deer mouse (Peromyscus) hybrids

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