Krüppel‐like factor 5 promotes mitosis by activating the cyclin B1/Cdc2 complex during oncogenic Ras‐mediated transformation

Nandan, Mandayam O.; Chanchevalap, Sengthong; Dalton, W. Brian; Yang, Vincent W.

doi:10.1016/j.febslet.2005.07.053

Cited by 78 publications

(86 citation statements)

References 45 publications

(75 reference statements)

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“…It is likely that one of the mechanisms in cancer cells is by deregulation of the cyclin B1 promoter so that there is a greater initiation of transcription (51). Another possible mechanism in cancer cells is the inhibition of cyclin B1 protein degradation, which is critical for progression through mitosis (2).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

Gomez

Pozas

Reiner³

et al. 2007

Molecular Cancer Therapeutics

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Chemotherapeutic drugs ideally should take advantage of the differences between transformed and normal cells and induce apoptosis only in cancer cells. One such difference may be the overexpression of cyclin B1 protein in cancer cells, which is required for the proper progression through mitosis. Previously, we showed that treatment of human prostate cancer cells with 2-methoxyestradiol (2-ME) or docetaxel results in an accumulation of cyclin B1 protein and an increase in cyclin B1 kinase activity, followed by induction of apoptotic cell death. Inhibition of cyclin B1 kinase lowers apoptosis induced by 2-ME and docetaxel. In this study, we established a positive correlation between cyclin B1 protein and apoptosis induced by chemotherapy in prostate cancer cells. There is minimal cyclin B1 and induction of apoptosis by chemotherapy in nontransformed cells. LNCaP and PC-3 prostate cancer cells stably overexpressing cyclin B1 are more sensitive to apoptosis induced by chemotherapy. LNCaP cells expressing cyclin B1 small interfering RNA to lower cyclin B1 protein or dominant negative cyclin-dependent kinase 1 to inhibit cyclin B1 kinase show a decrease in apoptosis. Increased sensitivity to apoptosis by overexpression of cyclin B1 may be due to lower Bcl-2, higher p53, and decreased neuroendocrine differentiation. We suggest that a cancer-specific mechanism whereby 2-ME and docetaxel may exert anti -prostate cancer activity is the deregulated activation of cyclin B1 kinase, leading to the induction of apoptotic cell death. Our results also suggest that higher levels of cyclin B1 in prostate cancer cells may be a good prognostic marker for chemotherapy. [Mol Cancer Ther 2007;6(5):1534 -43]

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Section: Discussionmentioning

confidence: 99%

Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

Gomez

Pozas

Reiner³

et al. 2007

Molecular Cancer Therapeutics

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“…This indicates that there could be some KLF5-independent mechanism. Careful interpretation of this molecular process is required as KLF5 may have various biological effects on cell growth (51,52) and secondary metabolic disturbances. Based on previous reports that Myc overexpression in transgenic mice contributed to glucose metabolism (53,54), it is possible that c-Myc, potentially induced by Fbw7i, could be involved in steatosis in Fbw7-knockdown livers.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice

Kumadaki

Karasawa

Matsuzaka

et al. 2011

Journal of Biological Chemistry

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F-box and WD repeat domain-containing 7 (Fbw7) is the component of an evolutionarily conserved complex of the Skp1-Cul1-F-box protein ubiquitin ligase and is involved in substrate recognition of the complex (1, 2). Fbw7 targets several proto-oncogenes that function in cell growth and division pathways, including c-Myc (encoded by Myc), cyclin E, Notch, and c-Jun (encoded by Jun) (3-7). Fbw7 is perturbed in many human malignancies and is an established tumor suppressor (8 -11). Mouse Fbw7 exists in three different isoforms as follows: ␣, ␤, and ␥. The ␣ isoform is expressed ubiquitously, whereas the ␤ and ␥ isoforms are expressed restrictedly in the brain, heart, testis, and skeletal muscle (12). Intriguing characteristics of Fbw7␣ (encoded by the isoform1 of Fbxw7) have recently been described by Ericsson et al. (13) who demonstrated that this cell growth regulator also regulated the degradation of the nuclear forms of the sterol regulatory elementbinding protein (SREBP) 2 family (14). SREBPs, belonging to the bHLH-Zip transcription factor family, are established regulators of lipid synthesis. The unique features of SREBPs are their rough-surfaced endoplasmic reticulum membrane-bound transcription factors. These factors need to undergo proteolytic cleavage for nuclear transport to activate the expression of genes involved in lipid synthesis. This represents the crucial step for sterol and fatty acid synthetic gene regulation (15)(16)(17). The SREBP family includes three isoforms as follows: . SREBP-2 governs cellular sterol regulation, whereas hepatic SREBP-1c (encoded by the isoformb of Srebf1) controls fatty acid and triglyceride synthesis depending on the nutritional state of the liver. SREBP-1a is highly expressed in growing cells and contributes to the synthesis of cholesterol, triglyceride (TG), and phospholipid for the supply of membrane lipids during cell growth (21, 22). Nuclear SREBP-1a regulates the cell cycle and growth by itself, indicating its strong association with cell growth (23,24).Without a proteasome inhibitor such as calpain inhibitor I in cell cultures, nuclear SREBPs are rapidly degraded by the ubiquitin-proteasome pathway after cleavage. Recently, Fbw7 was reported to be the key factor for this degradation of SREBPs in cultured cells (14). SREBP-1a is phosphorylated at several sites * This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental

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“…However, the identification of valid molecular targets remains a great challenge. Recently, Krüppel-like factor 5 (KLF5), a zinc finger transcription factor, has been shown to be involved in tumor progression, cell transformation, and angiogenesis (1)(2)(3)(4). This transcription factor is also known as an intestinal-enriched Krüppel-like factor and is predominantly present in the proliferating crypt epithelial cells of the intestine (5).…”

Section: Introductionmentioning

confidence: 99%

“…This is of particular interest, as recent studies showed that oncogenic HRAS may induce KLF5 overexpression through a mitogenactivated protein kinase (MAPK) signaling cascade, involving extracellular signal-regulated kinase (ERK) and early growth response gene 1 (4,10). Because pancreatic cancers frequently harbor activating KRAS mutations (11), which consecutively activate MEK/MAPK/Erk signaling (12), we hypothesized that KLF5 could be up-regulated in this cancer entity.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1α siRNA reduced constitutive KLF5. Similarly, KLF5 siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/ MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor

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Krüppel‐like factor 5 promotes mitosis by activating the cyclin B1/Cdc2 complex during oncogenic Ras‐mediated transformation

Cited by 78 publications

References 45 publications

Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Krüppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

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