The Experts below are selected from a list of 224037 Experts worldwide ranked by ideXlab platform
Ceshi Chen - One of the best experts on this subject based on the ideXlab platform.
-
YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
The American journal of pathology, 2012Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including Breast, ovarian, and hepatoCellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes Breast Cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP) and ITGB2. In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased Breast Cell proliferation and survival in MCF10A and SW527 Breast Cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as Cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative Breast Cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
-
TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation and tumorigenesis.
Carcinogenesis, 2011Co-Authors: Dong Zhao, Xu Zhi, Zhongmei Zhou, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells downregulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
-
Abstract LB-138: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation
Cellular and Molecular Biology, 2011Co-Authors: Dong Zhao, Xu Zhi, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitinated by E3 ubiquitin ligases, such as WWP1 and SCF Fbw7 . In this study, we demonstrate that transcriptional co-activator with PDZ binding motif (TAZ) upregulated KLF5 through antagonizing the WWP1-mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain and the PY motif, which is the binding site of WWP1. TAZ inhibited WWP1-mediated KLF5 ubiquitination and degradation. Overexpression of TAZ up-regulated the protein levels of KLF5 and FGF-BP, which is a well established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells dramatically down-regulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in SCID mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell proliferation through TAZ. Finally, both KLF5 and TAZ are co-expressed in a subset of ER-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation, and enhancing KLF59s activities. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2011-LB-138
-
Abstract LB-137: YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
Cellular and Molecular Biology, 2011Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP) is an oncoprotein in the Hippo tumor suppressor pathway that regulates tumorigenesis. Although YAP functions through its WW domains, the YAP WW domain binding partners have not been completely determined. In this study, we demonstrate that YAP functions partially through binding to KLF5, a transcription factor promoting Breast Cell proliferation and survival. YAP interacts with the KLF5 PY motif through its WW domains, prevents WWP1, a KLF5 E3 ubiquitin ligase, from binding to KLF5, and stabilizes KLF5 by decreasing the WWP1-mediated KLF5 ubiquitination and degradation. Over-expression of the wild type but not WW domain deficient YAP up-regulates the KLF5 protein levels and the mRNA expression levels of the KLF5 downstream target genes, including FGF-BP and ITGB2 . In addition, knockdown of YAP decreases the expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreases Breast Cell proliferation and survival in MCF10A and SW527 Breast Cells. Importantly, stable knockdown of YAP or KLF5 significantly suppresses SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppresses the KLF5-FGF-BP signaling axis and Cell growth through YAP. Finally, both YAP and KLF5 are co-expressed in estrogen receptor (ERα)-negative Breast Cell lines. These findings suggest that KLF5 is an important transcription factor partner for YAP and contributes to the Hippo tumor suppressor pathway. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-137. doi:10.1158/1538-7445.AM2011-LB-137
-
The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses Breast Cell proliferation.
Cancer research, 2010Co-Authors: Dong Zhao, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes Breast Cell proliferation and tumorigenesis through upregulating FGF-BP . The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF Fbw7 ) targets KLF5 for ubiquitin-mediated degradation in a GSK3β-mediated KLF5 phosphorylation–dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ( 303 S PPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and Breast Cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits Breast Cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for Breast cancer and other cancers. Cancer Res; 70(11); 4728–38. ©2010 AACR.
Dong Zhao - One of the best experts on this subject based on the ideXlab platform.
-
YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
The American journal of pathology, 2012Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including Breast, ovarian, and hepatoCellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes Breast Cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP) and ITGB2. In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased Breast Cell proliferation and survival in MCF10A and SW527 Breast Cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as Cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative Breast Cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
-
TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation and tumorigenesis.
Carcinogenesis, 2011Co-Authors: Dong Zhao, Xu Zhi, Zhongmei Zhou, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells downregulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
-
Abstract LB-138: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation
Cellular and Molecular Biology, 2011Co-Authors: Dong Zhao, Xu Zhi, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitinated by E3 ubiquitin ligases, such as WWP1 and SCF Fbw7 . In this study, we demonstrate that transcriptional co-activator with PDZ binding motif (TAZ) upregulated KLF5 through antagonizing the WWP1-mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain and the PY motif, which is the binding site of WWP1. TAZ inhibited WWP1-mediated KLF5 ubiquitination and degradation. Overexpression of TAZ up-regulated the protein levels of KLF5 and FGF-BP, which is a well established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells dramatically down-regulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in SCID mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell proliferation through TAZ. Finally, both KLF5 and TAZ are co-expressed in a subset of ER-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation, and enhancing KLF59s activities. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2011-LB-138
-
Abstract LB-137: YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
Cellular and Molecular Biology, 2011Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP) is an oncoprotein in the Hippo tumor suppressor pathway that regulates tumorigenesis. Although YAP functions through its WW domains, the YAP WW domain binding partners have not been completely determined. In this study, we demonstrate that YAP functions partially through binding to KLF5, a transcription factor promoting Breast Cell proliferation and survival. YAP interacts with the KLF5 PY motif through its WW domains, prevents WWP1, a KLF5 E3 ubiquitin ligase, from binding to KLF5, and stabilizes KLF5 by decreasing the WWP1-mediated KLF5 ubiquitination and degradation. Over-expression of the wild type but not WW domain deficient YAP up-regulates the KLF5 protein levels and the mRNA expression levels of the KLF5 downstream target genes, including FGF-BP and ITGB2 . In addition, knockdown of YAP decreases the expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreases Breast Cell proliferation and survival in MCF10A and SW527 Breast Cells. Importantly, stable knockdown of YAP or KLF5 significantly suppresses SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppresses the KLF5-FGF-BP signaling axis and Cell growth through YAP. Finally, both YAP and KLF5 are co-expressed in estrogen receptor (ERα)-negative Breast Cell lines. These findings suggest that KLF5 is an important transcription factor partner for YAP and contributes to the Hippo tumor suppressor pathway. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-137. doi:10.1158/1538-7445.AM2011-LB-137
-
The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses Breast Cell proliferation.
Cancer research, 2010Co-Authors: Dong Zhao, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes Breast Cell proliferation and tumorigenesis through upregulating FGF-BP . The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF Fbw7 ) targets KLF5 for ubiquitin-mediated degradation in a GSK3β-mediated KLF5 phosphorylation–dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ( 303 S PPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and Breast Cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits Breast Cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for Breast cancer and other cancers. Cancer Res; 70(11); 4728–38. ©2010 AACR.
Zhongmei Zhou - One of the best experts on this subject based on the ideXlab platform.
-
YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
The American journal of pathology, 2012Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including Breast, ovarian, and hepatoCellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes Breast Cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP) and ITGB2. In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased Breast Cell proliferation and survival in MCF10A and SW527 Breast Cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as Cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative Breast Cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
-
TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation and tumorigenesis.
Carcinogenesis, 2011Co-Authors: Dong Zhao, Xu Zhi, Zhongmei Zhou, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells downregulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
-
Abstract LB-137: YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
Cellular and Molecular Biology, 2011Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP) is an oncoprotein in the Hippo tumor suppressor pathway that regulates tumorigenesis. Although YAP functions through its WW domains, the YAP WW domain binding partners have not been completely determined. In this study, we demonstrate that YAP functions partially through binding to KLF5, a transcription factor promoting Breast Cell proliferation and survival. YAP interacts with the KLF5 PY motif through its WW domains, prevents WWP1, a KLF5 E3 ubiquitin ligase, from binding to KLF5, and stabilizes KLF5 by decreasing the WWP1-mediated KLF5 ubiquitination and degradation. Over-expression of the wild type but not WW domain deficient YAP up-regulates the KLF5 protein levels and the mRNA expression levels of the KLF5 downstream target genes, including FGF-BP and ITGB2 . In addition, knockdown of YAP decreases the expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreases Breast Cell proliferation and survival in MCF10A and SW527 Breast Cells. Importantly, stable knockdown of YAP or KLF5 significantly suppresses SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppresses the KLF5-FGF-BP signaling axis and Cell growth through YAP. Finally, both YAP and KLF5 are co-expressed in estrogen receptor (ERα)-negative Breast Cell lines. These findings suggest that KLF5 is an important transcription factor partner for YAP and contributes to the Hippo tumor suppressor pathway. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-137. doi:10.1158/1538-7445.AM2011-LB-137
-
The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses Breast Cell proliferation.
Cancer research, 2010Co-Authors: Dong Zhao, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes Breast Cell proliferation and tumorigenesis through upregulating FGF-BP . The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF Fbw7 ) targets KLF5 for ubiquitin-mediated degradation in a GSK3β-mediated KLF5 phosphorylation–dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ( 303 S PPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and Breast Cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits Breast Cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for Breast cancer and other cancers. Cancer Res; 70(11); 4728–38. ©2010 AACR.
-
klf5 promotes Breast Cell survival partially through fibroblast growth factor binding protein 1 perk mediated dual specificity mkp 1 protein phosphorylation and stabilization
Journal of Biological Chemistry, 2009Co-Authors: Rong Liu, Jin-tang Dong, Zhongmei Zhou, Hanqiu Zheng, Ceshi ChenAbstract:Krupple-like transcription factor 5 (KLF5) is a zinc-finger transcription factor promoting Cell survival and tumorigenesis in multiple cancers. A high expression level of KLF5 has been shown to be associated with shorter Breast cancer patient survival. However, the role of KLF5 and mechanism of KLF5 actions in Breast cancer remain unclear. In this study, we found that KLF5 knockdown by small interfering RNA in two Breast Cell lines, MCF10A and BT20, induces apoptosis. Interestingly, a pro-survival phosphatase, dual specificity mitogen-activated protein kinase phosphatase 1 (MKP-1), is down-regulated by KLF5 ablation. Consistently, KLF5 overexpression increases the MKP-1 protein expression in Hs578T and MCF7. We further found that MKP-1 is essential and sufficient for KLF5 to promote Breast Cell survival. However, MKP-1 is not a KLF5 direct transcription target because the MKP-1 mRNA level is not regulated by KLF5. By cycloheximide chase assays, we found that KLF5 decreases MKP-1 protein degradation via activating the ERK signaling. Inhibition of pERK by the pharmacological inhibitor U0126 specifically blocks KLF5-induced MKP-1 phosphorylation and stabilization. Additionally, constitutive activation of ERK by constitutively activated MEK1 rescues the KLF5 depletion-induced MKP-1 down-regulation. Consistently, the phosphorylation-deficient MKP-1 mutant cannot be stabilized by KLF5. Finally, the activation of ERK by KLF5 is very likely through the KLF5 direct target gene FGF-BP in Breast Cells. These findings suggest that KLF5 is a pro-survival factor that promotes Breast Cell survival partially through pERK-mediated MKP-1 phosphorylation and stabilization. The KLF5-FGF-BP-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive Breast cancer.
Xu Zhi - One of the best experts on this subject based on the ideXlab platform.
-
YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
The American journal of pathology, 2012Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP), an oncoprotein in the Hippo tumor suppressor pathway, regulates tumorigenesis and has been found in a variety of tumors, including Breast, ovarian, and hepatoCellular cancers. Although YAP functions through its WW domains, the YAP WW domain-binding partners have not yet been completely determined. With this study, we demonstrate that YAP functions partially through its binding to KLF5, a transcription factor that promotes Breast Cell proliferation and survival. YAP interacted with the KLF5 PY motif through its WW domains, preventing the E3 ubiquitin ligase WWP1 from ubiquitinating KLF5. Overexpression of the wild-type YAP but not the WW domain-mutated YAP up-regulated KLF5 protein levels and mRNA expression levels of KLF5 downstream target genes, including FGFBP1 (alias FGF-BP) and ITGB2. In addition, knockdown of YAP decreased expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreased Breast Cell proliferation and survival in MCF10A and SW527 Breast Cell lines, and stable knockdown of either YAP or KLF5 suppressed SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppressed the KLF5-FGF-BP axis, as well as Cell growth through YAP signaling. Both YAP and KLF5 are coexpressed in estrogen receptor ERα-negative Breast Cell lines. These findings suggest that KLF5 could be an important transcription factor partner for YAP and may contribute to the Hippo pathway.
-
TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation and tumorigenesis.
Carcinogenesis, 2011Co-Authors: Dong Zhao, Xu Zhi, Zhongmei Zhou, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells downregulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
-
Abstract LB-138: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes Breast Cell proliferation
Cellular and Molecular Biology, 2011Co-Authors: Dong Zhao, Xu Zhi, Ceshi ChenAbstract:Kruppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting Breast Cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitinated by E3 ubiquitin ligases, such as WWP1 and SCF Fbw7 . In this study, we demonstrate that transcriptional co-activator with PDZ binding motif (TAZ) upregulated KLF5 through antagonizing the WWP1-mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain and the PY motif, which is the binding site of WWP1. TAZ inhibited WWP1-mediated KLF5 ubiquitination and degradation. Overexpression of TAZ up-regulated the protein levels of KLF5 and FGF-BP, which is a well established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 Breast Cells dramatically down-regulated protein levels of KLF5 and FGF-BP and inhibited Cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in SCID mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted Cell proliferation through TAZ. Finally, both KLF5 and TAZ are co-expressed in a subset of ER-negative Breast Cell lines. These results, for the first time, suggest that TAZ promotes Breast Cell growth partially through protecting KLF5 from WWP1-mediated degradation, and enhancing KLF59s activities. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2011-LB-138
-
Abstract LB-137: YAP promotes Breast Cell proliferation and survival partially through stabilizing the KLF5 transcription factor
Cellular and Molecular Biology, 2011Co-Authors: Xu Zhi, Zhongmei Zhou, Dong Zhao, Rong Liu, Ceshi ChenAbstract:The Yes-associated protein (YAP) is an oncoprotein in the Hippo tumor suppressor pathway that regulates tumorigenesis. Although YAP functions through its WW domains, the YAP WW domain binding partners have not been completely determined. In this study, we demonstrate that YAP functions partially through binding to KLF5, a transcription factor promoting Breast Cell proliferation and survival. YAP interacts with the KLF5 PY motif through its WW domains, prevents WWP1, a KLF5 E3 ubiquitin ligase, from binding to KLF5, and stabilizes KLF5 by decreasing the WWP1-mediated KLF5 ubiquitination and degradation. Over-expression of the wild type but not WW domain deficient YAP up-regulates the KLF5 protein levels and the mRNA expression levels of the KLF5 downstream target genes, including FGF-BP and ITGB2 . In addition, knockdown of YAP decreases the expression levels of KLF5, FGF-BP, and ITGB2. Depletion of either YAP or KLF5 decreases Breast Cell proliferation and survival in MCF10A and SW527 Breast Cells. Importantly, stable knockdown of YAP or KLF5 significantly suppresses SW527 xenograft growth in mice. The YAP upstream kinase LATS1 suppresses the KLF5-FGF-BP signaling axis and Cell growth through YAP. Finally, both YAP and KLF5 are co-expressed in estrogen receptor (ERα)-negative Breast Cell lines. These findings suggest that KLF5 is an important transcription factor partner for YAP and contributes to the Hippo tumor suppressor pathway. This study is supported by a grant from the American Cancer Society (RSG-08–199–01) and a grant from the Department of Defense (W81XWH-07–1–0191). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-137. doi:10.1158/1538-7445.AM2011-LB-137
Edward J. Delikatny - One of the best experts on this subject based on the ideXlab platform.
-
Induction of magnetic resonance-visible lipid in a transformed human Breast Cell line by tetraphenylphosphonium chloride.
International Journal of Cancer, 1997Co-Authors: Sandrine K. Roman, Rebecca L. Hancock, Thomas M. Jeitner, Darryl C. Rideout, Wendy A. Cooper, Edward J. DelikatnyAbstract:Proton magnetic resonance spectroscopy (1H MRS) and DNA flow cytometry were used to monitor the effects of the cationic lipophilic phosphonium salt and potential antineoplastic agent tetraphenylphosphonium chloride (TPP) on the transformed human Breast Cell line HBL-100. TPP treatment for 48 hr was cytostatic at low concentrations and cytotoxic at higher concentrations with an IC50 of 55 μM as measured by Trypan blue exclusion. At micromolar concentrations, TPP caused a significant increase in the methylene MR signal arising from mobile lipid as measured by the ratio of the lipid CH2 peak height to either the CH3 peak height (internal referencing) or the peak height for p-aminobenzoic acid (PABA) as an external reference in a co-axial capillary within the sample. Over the same concentration range, TPP caused a slowing of passage through S phase as demonstrated by a significant depletion of Cells in G2/M phase with a concurrent but non-significant increase in Cells in S. Time-dependent increases in MR-visible lipid were observed with 2 μM TPP treatment, and the removal of TPP from the culture medium caused no significant reduction in mobile lipid. Two-dimensional 1H|Cv1H COSY spectra of TPP-treated HBL-100 Cells revealed concentration-dependent increases in cross-peak volume ratios arising from lipid acyl chains relative to both internal (lysine, polyamines) and external (PABA) standards. Increases in choline and glycerophosphocholine cross-peak volume ratios were observed, indicating that the catabolism or rearrangement of phospholipids may be responsible for the observed MR-visible lipid increases. Int. J. Cancer 73:570–579, 1997. © 1997 Wiley-Liss, Inc.
-
Tetraphenylphosphonium chloride induced mr-visible lipid accumulation in a malignant human Breast Cell line
International Journal of Cancer, 1996Co-Authors: Edward J. Delikatny, Sandrine K. Roman, Rebecca L. Hancock, Thomas M. Jeitner, Catherine M. Lander, Darryl C. Rideout, Carolyn E. MountfordAbstract:The effect of the cationic lipophilic phosphonium salt tetraphenylphosphonium chloride (TPP) on a human malignant Breast Cell line, DU4475, was monitored with proton nuclear magnetic resonance ( 1 H MRS). TPP caused a dose- and time-dependent increase in resonances arising from MR-visible lipid as measured by the CH 2 /CH 3 ratio in the 1-dimensional 1 H MR spectrum. Two-dimensional MRS identified increases in the glycerophosphocholine/lysine cross-peak ratio and corresponding decreases in the phosphocholine/lysine ratio in a dose-dependent fashion in TPP-treated Cells. Lipid metabolic changes are discussed in the light of other MR experiments, and the data indicate that accumulation of MR-visible lipids may arise from the rearrangement of phospholipids accompanying mitochondrial destruction or from the catabolism of phospholipids associated with early events in the cytotoxic process.