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Bertal H Aktas - One of the best experts on this subject based on the ideXlab platform.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27Kip1 plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27Kip1 expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27Kip1, however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27Kip1 mRNA. Specifically, human and mouse p27Kip1 mRNAs interact with HuR protein through multiple U-rich elements in both 5′ and 3′ untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27Kip1 mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27Kip1 mRNA and reduces its accumulation. We also identified a CT repeat in the 5′ UTR of full-length p27Kip1 mRNA isoforms that interact with a ∼41-kDa protein and represses p27Kip1 expression. This CT-rich element and diffuse elements in the 3′ UTR regulate post-transcriptional expression of p27Kip1 at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27Kip1 expression.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27(Kip1) plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27(Kip1) expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27(Kip1), however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27(Kip1) mRNA. Specifically, human and mouse p27(Kip1) mRNAs interact with HuR protein through multiple U-rich elements in both 5' and 3' untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27(Kip1) mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27(Kip1) mRNA and reduces its accumulation. We also identified a CT repeat in the 5' UTR of full-length p27(Kip1) mRNA isoforms that interact with a approximately 41-kDa protein and represses p27(Kip1) expression. This CT-rich element and diffuse elements in the 3' UTR regulate post-transcriptional expression of p27(Kip1) at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27(Kip1) expression.
Steffen Hauptmann - One of the best experts on this subject based on the ideXlab platform.
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expression of the elav like protein hur in human colon cancer association with cyclooxygenase 2 cox 2
Cancer Research, 2005Co-Authors: Carsten Denkert, Ines Koch, Manfred Dietel, Steffen Hauptmann, Aurelia Noske, Silvia Niesporek, Nora Von Keyserlingk, Wilko WeichertAbstract:1265 The human family of ELAV-like proteins consists of four members that are highly homologous to the drosophila nuclear protein embryonic-lethal Abnormal Vision (ELAV). One of these proteins, HuR, has been suggested to serve as a shuttling protein between the nucleus and the cytoplasm. In-vitro studies have shown that HuR is involved in regulation of mRNA stability of cyclooxygenase-2 (COX-2). In this study we investigated expression as well as cellular localization of HuR in a cohort of 87 primary colorectal adenocarcinomas as well as in three colon cancer cell lines (HRT-18, HT-29, CX-2). In addition, we investigated the expression of cyclooxygenase-2 in the primary colorectal carcinomas. Expression of the immunohistochemical markers was correlated with clinico-pathological parameters as well as with patient outcome. All cell lines showed an expression of HuR mRNA and protein by PCR and Western Blot. In the immunohistochemical study, we observed two different staining patterns of HuR in tumor tissue of colon carcinomas: A nuclear expression in 97% of cases as well as an additional cytoplasmic expression in 53% of cases. COX-2 was expressed in 63% of carcinomas. Cytoplasmic expression of HuR was significantly associated with increased COX-2 expression as well as with high tumor stage. In univariate Kaplan-Meier analysis, grading, tumor stage and nodal status but not HuR or COX-2 expression were prognostic factors for overall survival. Our results suggest that cytoplasmic overexpression of HuR in tissue of colorectal adenocarcinomas may regulate COX-2 protein levels. Thus, HuR may be part of a regulatory pathway that controls the mRNA stability of COX-2. Based on our results, further studies are necessary to investigate whether HuR might be a potential target for a molecular tumor therapy.
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expression of the elav like protein hur is associated with higher tumor grade and increased cyclooxygenase 2 expression in human breast carcinoma
Clinical Cancer Research, 2004Co-Authors: Carsten Denkert, Wilko Weichert, Manfred Dietel, K J Winzer, B M Muller, Aurelia Noske, Silvia Niesporek, Glen Kristiansen, Hans Guski, Steffen HauptmannAbstract:Purpose: The human ELAV (embryonic lethal Abnormal Vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3′-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. Experimental Design: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. Results: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression ( P P = 0.002) or nuclear HuR ( P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. Conclusions: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.
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overexpression of the embryonic lethal Abnormal Vision like protein hur in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression
Cancer Research, 2004Co-Authors: Carsten Denkert, Wilko Weichert, Soren Pest, Ines Koch, Dirk Licht, Martin Kobel, Angela Reles, Jalid Sehouli, Manfred Dietel, Steffen HauptmannAbstract:The human embryonic-lethal Abnormal Vision-like protein HuR is involved in the regulation of mRNA turnover and serves as a shuttling protein between the nucleus and the cytoplasm that stabilizes mRNAs containing adenine- and uridine-rich elements in their 3' untranslated region. We have shown recently that expression of cyclooxygenase (COX)-2 is related to poor prognosis in ovarian carcinoma. Other studies have shown that the COX-2 mRNA contains an adenine- and uridine-rich element and is stabilized by HuR. In this study, we investigated the expression and cellular distribution of HuR in 83 primary ovarian carcinomas, 16 borderline tumors of the ovary, 3 normal ovaries, and 9 ovarian carcinoma cell lines. Expression of HuR was detected in all cell lines on the mRNA and protein level and showed a predominantly nuclear staining in OVCAR-3 cells by confocal microscopy. In an immunohistochemical evaluation of human ovarian carcinomas, HuR showed a nuclear expression in 81% of tumors. In addition, a cytoplasmic expression of HuR was observed in a subgroup of 45% of ovarian carcinomas. Nuclear as well as cytoplasmic expression of HuR was significantly increased in ovarian carcinomas compared with borderline tumors or normal ovaries. In univariate analysis, a significant association between cytoplasmic HuR expression and increased COX-2 expression (P = 0.025) as well as between histological grade (P = 0.008) and mitotic activity (P = 0.002) was observed, although nuclear expression of HuR was not correlated with COX-2 expression or other clinicopathological parameters. In Kaplan-Meier survival analysis, increased cytoplasmic expression of HuR was a significant prognostic indicator for progression-free survival (P = 0.03) as well as overall survival (P = 0.007). In multivariate analysis using the Cox regression model, cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival with a relative risk of 2.62 (95% confidence interval, 1.32-5.19). Our results suggest that there is a dysregulation of cellular distribution of the mRNA stability factor HuR in a subset of invasive ovarian carcinomas. This dysregulation appears to result in an increased expression of COX-2, an increased proliferative rate, and may lead to a reduced survival time. Additional studies are required to analyze the downstream effects of increased cytoplasmic expression of HuR. In addition, it would be interesting to investigate the prognostic role of increased cytoplasmic expression of HuR in prospective studies.
Xuebin Qin - One of the best experts on this subject based on the ideXlab platform.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27Kip1 plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27Kip1 expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27Kip1, however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27Kip1 mRNA. Specifically, human and mouse p27Kip1 mRNAs interact with HuR protein through multiple U-rich elements in both 5′ and 3′ untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27Kip1 mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27Kip1 mRNA and reduces its accumulation. We also identified a CT repeat in the 5′ UTR of full-length p27Kip1 mRNA isoforms that interact with a ∼41-kDa protein and represses p27Kip1 expression. This CT-rich element and diffuse elements in the 3′ UTR regulate post-transcriptional expression of p27Kip1 at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27Kip1 expression.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27(Kip1) plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27(Kip1) expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27(Kip1), however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27(Kip1) mRNA. Specifically, human and mouse p27(Kip1) mRNAs interact with HuR protein through multiple U-rich elements in both 5' and 3' untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27(Kip1) mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27(Kip1) mRNA and reduces its accumulation. We also identified a CT repeat in the 5' UTR of full-length p27(Kip1) mRNA isoforms that interact with a approximately 41-kDa protein and represses p27(Kip1) expression. This CT-rich element and diffuse elements in the 3' UTR regulate post-transcriptional expression of p27(Kip1) at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27(Kip1) expression.
Jie Ming - One of the best experts on this subject based on the ideXlab platform.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27Kip1 plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27Kip1 expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27Kip1, however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27Kip1 mRNA. Specifically, human and mouse p27Kip1 mRNAs interact with HuR protein through multiple U-rich elements in both 5′ and 3′ untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27Kip1 mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27Kip1 mRNA and reduces its accumulation. We also identified a CT repeat in the 5′ UTR of full-length p27Kip1 mRNA isoforms that interact with a ∼41-kDa protein and represses p27Kip1 expression. This CT-rich element and diffuse elements in the 3′ UTR regulate post-transcriptional expression of p27Kip1 at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27Kip1 expression.
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embryonic lethal Abnormal Vision like hur dependent mrna stability regulates post transcriptional expression of cyclin dependent kinase inhibitor p27kip1
Journal of Biological Chemistry, 2010Co-Authors: Gudrun Ziegeler, Jie Ming, Jana C Koseki, Sema Sevinc, Ting Chen, Suleyman Ergun, Xuebin Qin, Bertal H AktasAbstract:The cyclin-dependent kinase inhibitor p27(Kip1) plays a critical role in regulating entry into and exit from the cell cycle. Post-transcriptional regulation of p27(Kip1) expression is of significant interest. The embryonic lethal Abnormal Vision (ELAV)-like RNA-binding protein HuR is thought be important for the translation of p27(Kip1), however, different reports attributed diametrically opposite roles to HuR. We report here an alternative mechanism wherein HuR regulates stability of the p27(Kip1) mRNA. Specifically, human and mouse p27(Kip1) mRNAs interact with HuR protein through multiple U-rich elements in both 5' and 3' untranslated regions (UTR). These interactions, which occur in vitro and in vivo, stabilize p27(Kip1) mRNA and play a critical role in its accumulation. Deleting HuR binding sites or knocking down HuR expression destabilizes p27(Kip1) mRNA and reduces its accumulation. We also identified a CT repeat in the 5' UTR of full-length p27(Kip1) mRNA isoforms that interact with a approximately 41-kDa protein and represses p27(Kip1) expression. This CT-rich element and diffuse elements in the 3' UTR regulate post-transcriptional expression of p27(Kip1) at the level of translation. This is the first demonstration that HuR-dependent mRNA stability and HuR-independent mRNA translation plays a critical role in the regulation of post-transcriptional p27(Kip1) expression.
Carsten Denkert - One of the best experts on this subject based on the ideXlab platform.
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expression of the elav like protein hur in human colon cancer association with cyclooxygenase 2 cox 2
Cancer Research, 2005Co-Authors: Carsten Denkert, Ines Koch, Manfred Dietel, Steffen Hauptmann, Aurelia Noske, Silvia Niesporek, Nora Von Keyserlingk, Wilko WeichertAbstract:1265 The human family of ELAV-like proteins consists of four members that are highly homologous to the drosophila nuclear protein embryonic-lethal Abnormal Vision (ELAV). One of these proteins, HuR, has been suggested to serve as a shuttling protein between the nucleus and the cytoplasm. In-vitro studies have shown that HuR is involved in regulation of mRNA stability of cyclooxygenase-2 (COX-2). In this study we investigated expression as well as cellular localization of HuR in a cohort of 87 primary colorectal adenocarcinomas as well as in three colon cancer cell lines (HRT-18, HT-29, CX-2). In addition, we investigated the expression of cyclooxygenase-2 in the primary colorectal carcinomas. Expression of the immunohistochemical markers was correlated with clinico-pathological parameters as well as with patient outcome. All cell lines showed an expression of HuR mRNA and protein by PCR and Western Blot. In the immunohistochemical study, we observed two different staining patterns of HuR in tumor tissue of colon carcinomas: A nuclear expression in 97% of cases as well as an additional cytoplasmic expression in 53% of cases. COX-2 was expressed in 63% of carcinomas. Cytoplasmic expression of HuR was significantly associated with increased COX-2 expression as well as with high tumor stage. In univariate Kaplan-Meier analysis, grading, tumor stage and nodal status but not HuR or COX-2 expression were prognostic factors for overall survival. Our results suggest that cytoplasmic overexpression of HuR in tissue of colorectal adenocarcinomas may regulate COX-2 protein levels. Thus, HuR may be part of a regulatory pathway that controls the mRNA stability of COX-2. Based on our results, further studies are necessary to investigate whether HuR might be a potential target for a molecular tumor therapy.
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expression of the elav like protein hur is associated with higher tumor grade and increased cyclooxygenase 2 expression in human breast carcinoma
Clinical Cancer Research, 2004Co-Authors: Carsten Denkert, Wilko Weichert, Manfred Dietel, K J Winzer, B M Muller, Aurelia Noske, Silvia Niesporek, Glen Kristiansen, Hans Guski, Steffen HauptmannAbstract:Purpose: The human ELAV (embryonic lethal Abnormal Vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3′-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. Experimental Design: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. Results: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression ( P P = 0.002) or nuclear HuR ( P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. Conclusions: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.
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overexpression of the embryonic lethal Abnormal Vision like protein hur in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression
Cancer Research, 2004Co-Authors: Carsten Denkert, Wilko Weichert, Soren Pest, Ines Koch, Dirk Licht, Martin Kobel, Angela Reles, Jalid Sehouli, Manfred Dietel, Steffen HauptmannAbstract:The human embryonic-lethal Abnormal Vision-like protein HuR is involved in the regulation of mRNA turnover and serves as a shuttling protein between the nucleus and the cytoplasm that stabilizes mRNAs containing adenine- and uridine-rich elements in their 3' untranslated region. We have shown recently that expression of cyclooxygenase (COX)-2 is related to poor prognosis in ovarian carcinoma. Other studies have shown that the COX-2 mRNA contains an adenine- and uridine-rich element and is stabilized by HuR. In this study, we investigated the expression and cellular distribution of HuR in 83 primary ovarian carcinomas, 16 borderline tumors of the ovary, 3 normal ovaries, and 9 ovarian carcinoma cell lines. Expression of HuR was detected in all cell lines on the mRNA and protein level and showed a predominantly nuclear staining in OVCAR-3 cells by confocal microscopy. In an immunohistochemical evaluation of human ovarian carcinomas, HuR showed a nuclear expression in 81% of tumors. In addition, a cytoplasmic expression of HuR was observed in a subgroup of 45% of ovarian carcinomas. Nuclear as well as cytoplasmic expression of HuR was significantly increased in ovarian carcinomas compared with borderline tumors or normal ovaries. In univariate analysis, a significant association between cytoplasmic HuR expression and increased COX-2 expression (P = 0.025) as well as between histological grade (P = 0.008) and mitotic activity (P = 0.002) was observed, although nuclear expression of HuR was not correlated with COX-2 expression or other clinicopathological parameters. In Kaplan-Meier survival analysis, increased cytoplasmic expression of HuR was a significant prognostic indicator for progression-free survival (P = 0.03) as well as overall survival (P = 0.007). In multivariate analysis using the Cox regression model, cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival with a relative risk of 2.62 (95% confidence interval, 1.32-5.19). Our results suggest that there is a dysregulation of cellular distribution of the mRNA stability factor HuR in a subset of invasive ovarian carcinomas. This dysregulation appears to result in an increased expression of COX-2, an increased proliferative rate, and may lead to a reduced survival time. Additional studies are required to analyze the downstream effects of increased cytoplasmic expression of HuR. In addition, it would be interesting to investigate the prognostic role of increased cytoplasmic expression of HuR in prospective studies.
