The Experts below are selected from a list of 270 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 microrna network in epithelial cancer cells
Current Genomics, 2013Co-Authors: Edward A RatovitskiAbstract:Non-coding microRNAs are involved in multiple regulatory mechanisms underlying response of cancer cells to stress leading to apoptosis, cell cycle arrest and autophagy. Many molecular layers are implicated in such cellular response including epigenetic regulation of transcription, RNA processing, metabolism, signaling. The molecular interrelationship between tumor Protein (TP)-p53 family members and specific microRNAs is a key functional network supporting tumor cell response to chemotherapy and potentially playing a decisive role in chemoresistance of human epithelial cancers. TP63 was shown to modulate the expression of numerous microRNAs involved in regulation of epithelial cell proliferation, differentiation, senescence, “stemness” and skin maintenance, epithelial/ mesenchymal transition, and tumorigenesis in several types of epithelial cancers (e.g. squamous cell carcinoma, ovarian carcinoma, prostate carcinoma, gastric cancer, bladder cancer, and breast tumors), as well as in chemoresistance of cancer cells. TP63/microRNA network was shown to be involved in cell cycle arrest, apoptosis, autophagy, metabolism and epigenetic transcriptional regulation, thereby providing the groundwork for novel chemotherapeutic venues.
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Tumor Protein P63/microRNA Network in Epithelial Cancer Cells.
Current Genomics, 2013Co-Authors: Edward A RatovitskiAbstract:Non-coding microRNAs are involved in multiple regulatory mechanisms underlying response of cancer cells to stress leading to apoptosis, cell cycle arrest and autophagy. Many molecular layers are implicated in such cellular response including epigenetic regulation of transcription, RNA processing, metabolism, signaling. The molecular interrelationship between tumor Protein (TP)-p53 family members and specific microRNAs is a key functional network supporting tumor cell response to chemotherapy and potentially playing a decisive role in chemoresistance of human epithelial cancers. TP63 was shown to modulate the expression of numerous microRNAs involved in regulation of epithelial cell proliferation, differentiation, senescence, “stemness” and skin maintenance, epithelial/ mesenchymal transition, and tumorigenesis in several types of epithelial cancers (e.g. squamous cell carcinoma, ovarian carcinoma, prostate carcinoma, gastric cancer, bladder cancer, and breast tumors), as well as in chemoresistance of cancer cells. TP63/microRNA network was shown to be involved in cell cycle arrest, apoptosis, autophagy, metabolism and epigenetic transcriptional regulation, thereby providing the groundwork for novel chemotherapeutic venues.
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Phospho‐ΔNP63α‐dependent microRNAs modulate chemoresistance of squamous cell carcinoma cells to cisplatin: At the crossroads of cell life and death
FEBS Letters, 2013Co-Authors: Edward A RatovitskiAbstract:The tumor Protein P63/microRNA functional network appears to play a decisive role in chemoresistance of human epithelial cancers. The cisplatin- and phosphorylated-ΔNP63α-dependent microRNAs, whose expression was varied in sensitive and resistant squamous cell carcinoma cells (SCC, which were derived from larynx and tongue tumors), were shown to modulate the expression of multiple members of cell cycle arrest, apoptosis and autophagy pathways. The specific microRNAs were further shown to modulate the resistant phenotype of SCC cells in vitro, thereby providing groundwork for novel chemotherapeutic venues for head and neck cancer.
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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-dependent regulation of autophagic signaling through transcription and micro-RNA modulation
Cell Cycle, 2012Co-Authors: Yiping Huang, Rafael Guerrero-preston, Edward A RatovitskiAbstract:Cisplatin was shown to induce the ataxia telangiectasia mutated (ATM)-dependent phosphorylation of tumor Protein P63 isoform, (ΔNP63α), leading to a transcriptional regulation of specific genes implicated in the control of cell death of squamous cell carcinoma (SCC) cells. We previously observed that the cisplatin-induced phosphorylated (p)-ΔNP63α transcriptionally regulates the expression of specific microRNAs (miRNAs) in SCC cells. We found here that cisplatin exposure of SCC cells led to modulation of the members of the autophagic pathway, such as Atg1/Ulk1, Atg3, Atg4A, Atg5, Atg6/Becn1, Atg7, Atg9A and Atg10, by a direct p-ΔNP63α-dependent transcriptional regulation. We further found that specific miRNAs (miR-181a, miR-519a, miR-374a and miR-630), which are critical downstream targets of the p-ΔNP63α, modulated the Protein levels of ATG5, ATG6/BECN1, ATG10, ATG12, ATG16L1 and UVRAG, adding another level of expression control for autophagic pathways in SCC cells upon cisplatin exposure. Our data suppo...
David A Thorleylawson - One of the best experts on this subject based on the ideXlab platform.
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processing of the epstein barr virus encoded latent membrane Protein P63 lmp
Journal of Virology, 1990Co-Authors: Ramkumar Moorthy, David A ThorleylawsonAbstract:We have analyzed the processing of the Epstein-Barr virus-encoded latent membrane Protein (P63/LMP) in lymphoblastoid cell lines, Burkitt's lymphoma cell lines, and rodent fibroblasts transfected with the P63/LMP gene. Pulse-chase analysis by immunoprecipitation, under denaturing conditions, reveals a half-life of 2 h. This is due to turnover in the plasma membrane with cleavage of the Protein, resulting in a 25,000-molecular-weight (p25) fragment derived from the carboxy-terminal portion of LMP. This fragment is rich in proline and acidic amino acids and sheds into the cytoplasm, where it appears to accumulate, being present in a six- to sevenfold molar excess over P63/LMP in immunoprecipitation analyses. p25 is, like P63/LMP, also phosphorylated (pp25) on serine and threonine residues, in the same ratio and to approximately the same extent as the intact P63/LMP molecule. Amino acid sequence analysis and carboxy-terminal labeling suggest that p25 is derived through a single cleavage adjacent to the sequence LGAPGGGPDNGPQDPD.
Ramkumar Moorthy - One of the best experts on this subject based on the ideXlab platform.
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processing of the epstein barr virus encoded latent membrane Protein P63 lmp
Journal of Virology, 1990Co-Authors: Ramkumar Moorthy, David A ThorleylawsonAbstract:We have analyzed the processing of the Epstein-Barr virus-encoded latent membrane Protein (P63/LMP) in lymphoblastoid cell lines, Burkitt's lymphoma cell lines, and rodent fibroblasts transfected with the P63/LMP gene. Pulse-chase analysis by immunoprecipitation, under denaturing conditions, reveals a half-life of 2 h. This is due to turnover in the plasma membrane with cleavage of the Protein, resulting in a 25,000-molecular-weight (p25) fragment derived from the carboxy-terminal portion of LMP. This fragment is rich in proline and acidic amino acids and sheds into the cytoplasm, where it appears to accumulate, being present in a six- to sevenfold molar excess over P63/LMP in immunoprecipitation analyses. p25 is, like P63/LMP, also phosphorylated (pp25) on serine and threonine residues, in the same ratio and to approximately the same extent as the intact P63/LMP molecule. Amino acid sequence analysis and carboxy-terminal labeling suggest that p25 is derived through a single cleavage adjacent to the sequence LGAPGGGPDNGPQDPD.
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Processing of the Epstein-Barr virus-encoded latent membrane Protein P63/LMP.
Journal of Virology, 1990Co-Authors: Ramkumar Moorthy, David A. Thorley-lawsonAbstract:We have analyzed the processing of the Epstein-Barr virus-encoded latent membrane Protein (P63/LMP) in lymphoblastoid cell lines, Burkitt's lymphoma cell lines, and rodent fibroblasts transfected with the P63/LMP gene. Pulse-chase analysis by immunoprecipitation, under denaturing conditions, reveals a half-life of 2 h. This is due to turnover in the plasma membrane with cleavage of the Protein, resulting in a 25,000-molecular-weight (p25) fragment derived from the carboxy-terminal portion of LMP. This fragment is rich in proline and acidic amino acids and sheds into the cytoplasm, where it appears to accumulate, being present in a six- to sevenfold molar excess over P63/LMP in immunoprecipitation analyses. p25 is, like P63/LMP, also phosphorylated (pp25) on serine and threonine residues, in the same ratio and to approximately the same extent as the intact P63/LMP molecule. Amino acid sequence analysis and carboxy-terminal labeling suggest that p25 is derived through a single cleavage adjacent to the sequence LGAPGGGPDNGPQDPD.
Hanspeter Hauri - One of the best experts on this subject based on the ideXlab platform.
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Retention of P63 in an ER-Golgi intermediate compartment depends on the presence of all three of its domains and on its ability to form oligomers.
Journal of Cell Biology, 1994Co-Authors: Anja Schweizer, Jack Rohrer, Hanspeter Hauri, Stuart KornfeldAbstract:The type II membrane Protein P63 is a resident Protein of a membrane network interposed between rough ER and Golgi apparatus. To study the retention of P63, mutant forms were expressed in COS cells and the intracellular distribution determined by immunofluorescence microscopy. Investigation of chimeric constructs between P63 and the plasma membrane Protein dipeptidylpeptidase IV showed that Protein sequences from all three domains of the P63 Protein are required to achieve complete intracellular retention. Mutational analysis of the 106-amino acid cytoplasmic tail of P63 revealed that the NH2-terminal 23 amino acids are necessary for retention. When P63 was solubilized with Triton X-100 and subjected to centrifugation at 100,000 g, it formed large, insoluble oligomers, particularly at neutral pH and below. A comparison of the behavior of wildtype and mutant P63 Proteins in this assay revealed a perfect correlation between the formation of large oligomers and correct intracellular retention. These results suggest that self-association may be a major mechanism by which P63 is retained between the rough ER and the Golgi apparatus.
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Implications for the organization of the ER-to-Golgi pathway
1993Co-Authors: Anja Schweizer, Maria Ericsson, Thomas Bächi, Gareth Griffiths, Hanspeter HauriAbstract:Owing to the lack of appropriate markers the structural organization of the ER-to-Golgi pathway and the dynamics of its membrane elements have been elusive. To elucidate this organization we have taken a mono clonal antibody (mAb) approach. A mAb against a novel 63 kDa membrane Protein (P63) was produced that identifies a large tubular network of smooth membranes in the cytoplasm of primate cells. The distribution of P63 overlaps with the ER-Golgi intermediate compartment, defined by a previously described 53 kDa marker Protein (here termed ERGIC-53), as visualized by confocal laser scanning immunofluorescence microscopy and immunoelectron microscopy. The P63 compartment mediates Protein transport from the ER to Golgi apparatus, as indicated by partial colocalization of P63 and vesicular stomatitis virus G Protein in Vero cells cul tured at 15°C. Low temperatures and brefeldin A had little effect on the cellular distribution of P63, suggest ing that this novel marker is a stably anchored resident Protein of these pre-Golgi membranes. P63 and ERGIC53 were enriched to a similar degree by the same sub cellular fractionation procedure. These findings demonstrate an unanticipated complexity of the ER-Golgi interface and suggest that the ER-Golgi intermediate compartment defined by ERGIC-53 may be part of a greater network of smooth membranes.
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a reversibly palmitoylated resident Protein P63 of an er golgi intermediate compartment is related to a circulatory shock resuscitation Protein
Journal of Cell Science, 1993Co-Authors: Anja Schweizer, Jack Rohrer, Paul Jeno, Antonio Demaio, Timothy G Buchman, Hanspeter HauriAbstract:The recently identified 63 kDa membrane Protein, P63, is a resident Protein of a membrane network interposed in between rough ER and Golgi apparatus. To characterize P63 at the molecular level a 2.91 kb cDNA encoding P63 has been isolated from a human placenta lambda gt10 cDNA library. Sequence analysis of tryptic peptides prepared from isolated P63 confirmed the identify of the cloned gene. The translated amino acid sequence consists of 601 amino acids (65.8 kDa) with a single putative membrane-spanning region and a N-terminal cytoplasmic domain of 106 amino acids. The human P63 cDNA exhibits a high level of sequence identify to the pig hepatic cDNA 3AL (accession number M27092) whose expression is enhanced after resuscitation from circulatory shock. An additional remarkable feature of P63 is that it becomes reversibly palmitoylated when intracellular Protein transport is blocked by the drug brefeldin A. Overexpression of P63 in COS cells led to the development of a striking tubular membrane network in the cytoplasm. This suggests that the Protein may be determinant for the structure of the P63 compartment.
Anja Schweizer - One of the best experts on this subject based on the ideXlab platform.
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Retention of P63 in an ER-Golgi intermediate compartment depends on the presence of all three of its domains and on its ability to form oligomers.
Journal of Cell Biology, 1994Co-Authors: Anja Schweizer, Jack Rohrer, Hanspeter Hauri, Stuart KornfeldAbstract:The type II membrane Protein P63 is a resident Protein of a membrane network interposed between rough ER and Golgi apparatus. To study the retention of P63, mutant forms were expressed in COS cells and the intracellular distribution determined by immunofluorescence microscopy. Investigation of chimeric constructs between P63 and the plasma membrane Protein dipeptidylpeptidase IV showed that Protein sequences from all three domains of the P63 Protein are required to achieve complete intracellular retention. Mutational analysis of the 106-amino acid cytoplasmic tail of P63 revealed that the NH2-terminal 23 amino acids are necessary for retention. When P63 was solubilized with Triton X-100 and subjected to centrifugation at 100,000 g, it formed large, insoluble oligomers, particularly at neutral pH and below. A comparison of the behavior of wildtype and mutant P63 Proteins in this assay revealed a perfect correlation between the formation of large oligomers and correct intracellular retention. These results suggest that self-association may be a major mechanism by which P63 is retained between the rough ER and the Golgi apparatus.
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Implications for the organization of the ER-to-Golgi pathway
1993Co-Authors: Anja Schweizer, Maria Ericsson, Thomas Bächi, Gareth Griffiths, Hanspeter HauriAbstract:Owing to the lack of appropriate markers the structural organization of the ER-to-Golgi pathway and the dynamics of its membrane elements have been elusive. To elucidate this organization we have taken a mono clonal antibody (mAb) approach. A mAb against a novel 63 kDa membrane Protein (P63) was produced that identifies a large tubular network of smooth membranes in the cytoplasm of primate cells. The distribution of P63 overlaps with the ER-Golgi intermediate compartment, defined by a previously described 53 kDa marker Protein (here termed ERGIC-53), as visualized by confocal laser scanning immunofluorescence microscopy and immunoelectron microscopy. The P63 compartment mediates Protein transport from the ER to Golgi apparatus, as indicated by partial colocalization of P63 and vesicular stomatitis virus G Protein in Vero cells cul tured at 15°C. Low temperatures and brefeldin A had little effect on the cellular distribution of P63, suggest ing that this novel marker is a stably anchored resident Protein of these pre-Golgi membranes. P63 and ERGIC53 were enriched to a similar degree by the same sub cellular fractionation procedure. These findings demonstrate an unanticipated complexity of the ER-Golgi interface and suggest that the ER-Golgi intermediate compartment defined by ERGIC-53 may be part of a greater network of smooth membranes.
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a reversibly palmitoylated resident Protein P63 of an er golgi intermediate compartment is related to a circulatory shock resuscitation Protein
Journal of Cell Science, 1993Co-Authors: Anja Schweizer, Jack Rohrer, Paul Jeno, Antonio Demaio, Timothy G Buchman, Hanspeter HauriAbstract:The recently identified 63 kDa membrane Protein, P63, is a resident Protein of a membrane network interposed in between rough ER and Golgi apparatus. To characterize P63 at the molecular level a 2.91 kb cDNA encoding P63 has been isolated from a human placenta lambda gt10 cDNA library. Sequence analysis of tryptic peptides prepared from isolated P63 confirmed the identify of the cloned gene. The translated amino acid sequence consists of 601 amino acids (65.8 kDa) with a single putative membrane-spanning region and a N-terminal cytoplasmic domain of 106 amino acids. The human P63 cDNA exhibits a high level of sequence identify to the pig hepatic cDNA 3AL (accession number M27092) whose expression is enhanced after resuscitation from circulatory shock. An additional remarkable feature of P63 is that it becomes reversibly palmitoylated when intracellular Protein transport is blocked by the drug brefeldin A. Overexpression of P63 in COS cells led to the development of a striking tubular membrane network in the cytoplasm. This suggests that the Protein may be determinant for the structure of the P63 compartment.
