The Experts below are selected from a list of 180546 Experts worldwide ranked by ideXlab platform
Edward A. Ratovitski - One of the best experts on this subject based on the ideXlab platform.
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tumor protein p63 is a key regulator of skin functions in ectodermal dysplasia
2013Co-Authors: Edward A. RatovitskiAbstract:Tumor protein (TP)-p63 has been discovered as TP53 homolog more than fifteen years ago and has become a master regulator of skin development, proliferation and stem cell maintenance. While TP53 is known to be the most mutated gene in human cancer, TP63 mutations are mostly associated with the various types of ectodermal dysplasia. All TP53 family members, TP53, TP63 and TP73, function as transcription factors that regulate the cell cycle arrest, apoptosis, autophagy or metabolism through activation/repression of downstream target genes or protein-protein interactions with other protein regulators of transcription and splicing. Several downstream target genes or protein interactors of TP63 are involved in the molecular mechanisms underlying the ectodermal dysplasia phenotypes. This mini-review underlines a few venues of investigations about the key role for TP63 in skin biology and pathology.
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phospho δnp63α srebf1 protein interactions bridging cell metabolism and cisplatin chemoresistance
Cell Cycle, 2012Co-Authors: Yiping Huang, Lauren N Bell, Jun Okamura, Myoung Soo Kim, Robert P Mohney, Rafael Guerreropreston, Edward A. RatovitskiAbstract:Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the ATM-dependent phosphorylation of ΔNp63α (p-ΔNp63α), which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p-ΔNp63α became more cisplatin-resistant. We also found that p-ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifications. Here, we showed that p-ΔNp63α induced ARG1, GAPDH, and CPT2 gene transcription in cisplatin-sensitive SCC cells, while non-p-ΔNp63α increased a transcription of CAD, G6PD and FASN genes in cisplatin-resistant SCC cells. We report that the p-ΔNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby affect tumor cell response to cisplatin-induced cell death, suggesting that the ATM-dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Yiping Huang, Debasish Sinha, Edward A. Ratovitski, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor kappa B (NF-kappa B) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-kappa B activation leads to the reduction of the TP63 isoform, Delta Np63 alpha, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-kappa B is poorly understood. Here, we report that the TAp63 regulates NF-kappa B transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63 beta induced the expression of the p65 subunit of NF-kappa B (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63 beta-dependent regulation of cell death. We showed that TAp63 beta and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63 beta directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-kappa B-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63 beta and NF-kappa B involved in the activation of cell death process of cancer cells.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Tanusree Sen, Debasish Sinha, Edward A. Ratovitski, Yiping Huang, Nilkantha Sen, Zhen Ge Luo, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor κB (NF-κB) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-κB activation leads to the reduction of the TP63 isoform, ΔNp63α, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-κB is poorly understood. Here, we report that the TAp63 regulates NF-κB transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63α induced the expression of the p65 subunit of NF-κB (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63α-dependent regulation of cell death. We showed that TAp63α and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63α directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-κB-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63α and NF-κB involved in the activation of cell death process of cancer cells.
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international research symposium on ankyloblepharon ectodermal defects cleft lip palate aec syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Hans Vanbokhoven, Suzanne E Clements, Frank Mckeon, Dennis R Roop, Caterina Missero, Vivian A Lombillo, Edward A. RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.
Meredith Wilson - One of the best experts on this subject based on the ideXlab platform.
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recurrence of split hand foot malformation cleft lip palate and severe urogenital abnormalities due to germline mosaicism for TP63 mutation
American Journal of Medical Genetics Part A, 2016Co-Authors: Annabelle Enriquez, Michael Krivanek, Ricarda Flottmann, Hartmut Peters, Meredith WilsonAbstract:: We describe two sibling fetuses with urogenital abnormalities detected by prenatal ultrasound, in which post-delivery examination showed split hand and foot malformation, and bilateral cleft lip and palate. These findings are consistent with ectrodactyly-ectodermal dysplasia-cleft lip with or without cleft palate syndrome (EEC). Both fetuses were found to have the same missense mutation in TP63 (c.1051G > A; p.D351N). Parental clinical examinations and lymphocyte DNA analyses were normal. This report illustrates the potential severity of urogenital defects in TP63-related disorders, which may be detectable with fetal ultrasonography. It highlights the need to counsel for the possibility of germline mosaicism in TP63-associated disorders. © 2016 Wiley Periodicals, Inc.
David Sidransky - One of the best experts on this subject based on the ideXlab platform.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Yiping Huang, Debasish Sinha, Edward A. Ratovitski, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor kappa B (NF-kappa B) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-kappa B activation leads to the reduction of the TP63 isoform, Delta Np63 alpha, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-kappa B is poorly understood. Here, we report that the TAp63 regulates NF-kappa B transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63 beta induced the expression of the p65 subunit of NF-kappa B (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63 beta-dependent regulation of cell death. We showed that TAp63 beta and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63 beta directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-kappa B-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63 beta and NF-kappa B involved in the activation of cell death process of cancer cells.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Tanusree Sen, Debasish Sinha, Edward A. Ratovitski, Yiping Huang, Nilkantha Sen, Zhen Ge Luo, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor κB (NF-κB) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-κB activation leads to the reduction of the TP63 isoform, ΔNp63α, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-κB is poorly understood. Here, we report that the TAp63 regulates NF-κB transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63α induced the expression of the p65 subunit of NF-κB (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63α-dependent regulation of cell death. We showed that TAp63α and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63α directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-κB-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63α and NF-κB involved in the activation of cell death process of cancer cells.
Laura D Attardi - One of the best experts on this subject based on the ideXlab platform.
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differential perp regulation by TP63 mutants provides insight into aec pathogenesis
American Journal of Medical Genetics Part A, 2009Co-Authors: Veronica G Beaudry, Navneeta Pathak, Maranke I. Koster, Laura D AttardiAbstract:Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay-Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell-cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC.
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international research symposium on ankyloblepharon ectodermal defects cleft lip palate aec syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Hans Vanbokhoven, Suzanne E Clements, Frank Mckeon, Dennis R Roop, Caterina Missero, Vivian A Lombillo, Edward A. RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.
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International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome.
American Journal of Medical Genetics Part A, 2009Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Hans Vanbokhoven, Suzanne E Clements, Frank Mckeon, Dennis R Roop, Caterina Missero, Vivian A Lombillo, Edward A. RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (Hay-Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related syndromes.
Yiping Huang - One of the best experts on this subject based on the ideXlab platform.
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phospho δnp63α srebf1 protein interactions bridging cell metabolism and cisplatin chemoresistance
Cell Cycle, 2012Co-Authors: Yiping Huang, Lauren N Bell, Jun Okamura, Myoung Soo Kim, Robert P Mohney, Rafael Guerreropreston, Edward A. RatovitskiAbstract:Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the ATM-dependent phosphorylation of ΔNp63α (p-ΔNp63α), which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p-ΔNp63α became more cisplatin-resistant. We also found that p-ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifications. Here, we showed that p-ΔNp63α induced ARG1, GAPDH, and CPT2 gene transcription in cisplatin-sensitive SCC cells, while non-p-ΔNp63α increased a transcription of CAD, G6PD and FASN genes in cisplatin-resistant SCC cells. We report that the p-ΔNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby affect tumor cell response to cisplatin-induced cell death, suggesting that the ATM-dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Yiping Huang, Debasish Sinha, Edward A. Ratovitski, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor kappa B (NF-kappa B) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-kappa B activation leads to the reduction of the TP63 isoform, Delta Np63 alpha, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-kappa B is poorly understood. Here, we report that the TAp63 regulates NF-kappa B transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63 beta induced the expression of the p65 subunit of NF-kappa B (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63 beta-dependent regulation of cell death. We showed that TAp63 beta and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63 beta directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-kappa B-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63 beta and NF-kappa B involved in the activation of cell death process of cancer cells.
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tumor protein p63 nuclear factor κb feedback loop in regulation of cell death
Journal of Biological Chemistry, 2011Co-Authors: Tanusree Sen, Debasish Sinha, Edward A. Ratovitski, Yiping Huang, Nilkantha Sen, Zhen Ge Luo, David SidranskyAbstract:Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor κB (NF-κB) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-κB activation leads to the reduction of the TP63 isoform, ΔNp63α, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-κB is poorly understood. Here, we report that the TAp63 regulates NF-κB transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63α induced the expression of the p65 subunit of NF-κB (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63α-dependent regulation of cell death. We showed that TAp63α and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63α directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-κB-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63α and NF-κB involved in the activation of cell death process of cancer cells.
