The Experts below are selected from a list of 53661 Experts worldwide ranked by ideXlab platform
Gunnar Westin - One of the best experts on this subject based on the ideXlab platform.
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Mutational Analysis of p27 cdkn1b and p18 cdkn2c in sporadic pancreatic endocrine tumors argues against tumor suppressor function
Neoplasia, 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
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Mutational Analysis of p27 (CDKN1B) and p18 (CDKN2C) in sporadic pancreatic endocrine tumors argues against tumor-suppressor function.
Neoplasia (New York N.Y.), 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
John A Tainer - One of the best experts on this subject based on the ideXlab platform.
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crystal structure and Mutational Analysis of the human cdk2 kinase complex with cell cycle regulatory protein ckshs1
Cell, 1996Co-Authors: Yves Bourne, Mark H Watson, Michael J Hickey, William D Holmes, Warren J Rocque, Steven I Reed, John A TainerAbstract:Abstract The 2.6 A crystal structure for human cyclin-dependent kinase 2 (CDK2) in complex with CksHs1, a human homolog of essential yeast cell cycle–regulatory proteins suc1 and Cks1, reveals that CksHs1 binds via all four β strands to the kinase C-terminal lobe. This interface is biologically critical, based upon Mutational Analysis, but far from the CDK2 N-terminal lobe, cyclin, and regulatory phosphorylation sites. CDK2 binds the Cks single domain conformation and interacts with conserved hydrophobic residues plus His-60 and Glu-63 in their closed β-hinge motif conformation. The β hinge opening to form the Cks β-interchanged dimer sterically precludes CDK2 binding, providing a possible mechanism regulating CDK2–Cks interactions. One face of the complex exposes the sequence-conserved phosphate-binding region on Cks and the ATP-binding site on CDK2, suggesting that Cks may target CDK2 to other phosphoproteins during the cell cycle.
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crystal structure and Mutational Analysis of human uracil dna glycosylase structural basis for specificity and catalysis
Cell, 1995Co-Authors: Clifford D Mol, Andrew S Arvai, Geir Slupphaug, Bodil Kavli, Ingrun Alseth, Hans E Krokan, John A TainerAbstract:Crystal structures of the DNA repair enzyme human uracil-DNA glycosylase (UDG), combined with Mutational Analysis, reveal the structural basis for the specificity of the enzyme. Within the classic alpha/beta fold of UDG, sequence-conserved residues form a positively charged, active-site groove the width of duplex DNA, at the C-terminal edge of the central four-stranded parallel beta sheet. In the UDG-6-aminouracil complex, uracil binds at the base of the groove within a rigid preformed pocket that confers selectivity for uracil over other bases by shape complementary and by main chain and Asn-204 side chain hydrogen bonds. Main chain nitrogen atoms are positioned to stabilize the oxyanion intermediate generated by His-268 acting via nucleophilic attack or general base mechanisms. Specific binding of uracil flipped out from a DNA duplex provides a structural mechanism for damaged base recognition.
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crystal structure and Mutational Analysis of human uracil dna glycosylase structural basis for specificity and catalysis
Cell, 1995Co-Authors: Andrew S Arvai, Geir Slupphaug, Bodil Kavli, Ingrun Alseth, Hans E Krokan, John A TainerAbstract:Abstract Crystal structures of the DNA repair enzyme human uracil-DNA glycosylase (UDG), combined with Mutational Analysis, reveal the structural basis for the specificity of the enzyme. Within the classic α/β fold of UDG, sequence-conserved residues form a positively charged, active-site groove the width of duplex DNA, at the C-terminal edge of the central four-stranded parallel β sheet. In the UDG-6-aminouracil complex, uracil binds at the base of the groove within a rigid preformed pocket that confers selectivity for uracil over other bases by shape complementarity and by main chain and Asn-204 side chain hydrogen bonds. Main chain nitrogen atoms are positioned to stabilize the oxyanion intermediate generated by His-268 acting via nucleophilic attack or general base mechanisms. Specific binding of uracil flipped out from a DNA duplex provides a structural mechanism for damaged base recognition.
Daniel Lindberg - One of the best experts on this subject based on the ideXlab platform.
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Mutational Analysis of p27 cdkn1b and p18 cdkn2c in sporadic pancreatic endocrine tumors argues against tumor suppressor function
Neoplasia, 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
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Mutational Analysis of p27 (CDKN1B) and p18 (CDKN2C) in sporadic pancreatic endocrine tumors argues against tumor-suppressor function.
Neoplasia (New York N.Y.), 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
Joseph G Hacia - One of the best experts on this subject based on the ideXlab platform.
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comparisons of substitution insertion and deletion probes for resequencing and Mutational Analysis using oligonucleotide microarrays
Nucleic Acids Research, 2005Co-Authors: Mazen W Karaman, Brian L Pike, Susan Groshen, Joseph G HaciaAbstract:Although oligonucleotide probes complementary to single nucleotide substitutions are commonly used in microarray-based screens for genetic variation, little is known about the hybridization properties of probes complementary to small insertions and deletions. It is necessary to define the hybridization properties of these latter probes in order to improve the specificity and sensitivity of oligonucleotide microarray-based Mutational Analysis of disease-related genes. Here, we compare and contrast the hybridization properties of oligonucleotide microarrays consisting of 25mer probes complementary to all possible single nucleotide substitutions and insertions, and one and two base deletions in the 9168 bp coding region of the ATM (ataxia telangiectasia mutated) gene. Over 68 different dye-labeled single-stranded nucleic acid targets representing all ATM coding exons were applied to these microarrays. We assess hybridization specificity by comparing the relative hybridization signals from probes perfectly matched to ATM sequences to those containing mismatches. Probes complementary to two base substitutions displayed the highest average specificity followed by those complementary to single base substitutions, single base deletions and single base insertions. In all the cases, hybridization specificity was strongly influenced by sequence context and possible intra- and intermolecular probe and/or target structure. Furthermore, single nucleotide substitution probes displayed the most consistent hybridization specificity data followed by single base deletions, two base deletions and single nucleotide insertions. Overall, these studies provide valuable empirical data that can be used to more accurately model the hybridization properties of insertion and deletion probes and improve the design and interpretation of oligonucleotide microarray-based resequencing and Mutational Analysis.
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Mutational Analysis using oligonucleotide microarrays
Journal of Medical Genetics, 1999Co-Authors: Joseph G Hacia, Francis S. CollinsAbstract:The development of inexpensive high throughput methods to identify individual DNA sequence differences is important to the future growth of medical genetics. This has become increasingly apparent as epidemiologists, pathologists, and clinical geneticists focus more attention on the molecular basis of complex multifactorial diseases. Such undertakings will rely upon genetic maps based upon newly discovered, common, single nucleotide polymorphisms. Furthermore, candidate gene approaches used in identifying disease associated genes necessitate screening large sequence blocks for changes tracking with the disease state. Even after such genes are isolated, large scale Mutational analyses will often be needed for risk assessment studies to define the likely medical consequences of carrying a mutated gene. This review concentrates on the use of oligonucleotide arrays for hybridisation based comparative sequence Analysis. Technological advances within the past decade have made it possible to apply this technology to many different aspects of medical genetics. These applications range from the detection and scoring of single nucleotide polymorphisms to Mutational Analysis of large genes. Although we discuss published scientific reports, unpublished work from the private sector1 2 could also significantly affect the future of this technology.
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resequencing and Mutational Analysis using oligonucleotide microarrays
Nature Genetics, 1999Co-Authors: Joseph G HaciaAbstract:Oligonucleotide microarray (DNA chip)–based hybridization Analysis is a promising new technology which potentially allows rapid and cost–effective screens for all possible mutations and sequence variations in genomic DNA. Here, I review current strategies and uses for DNA chip–based resequencing and Mutational Analysis, the underlying principles of experimental designs, and future efforts to improve the sensitivity and specificity of chip–based assays.
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strategies for Mutational Analysis of the large multiexon atm gene using high density oligonucleotide arrays
Genome Research, 1998Co-Authors: Joseph G Hacia, Christiane M Robbins, Bryan K Sun, Nathaniel Hunt, Keith Edgemon, Deborah Mosbrook, Stephen P A Fodor, Danilo A Tagle, Francis S. CollinsAbstract:Mutational Analysis of large genes with complex genomic structures plays an important role in medical genetics. Technical limitations associated with current mutation screening protocols have placed increased emphasis on the development of new technologies to simplify these procedures. High-density arrays of >90,000-oligonucleotide probes, 25 nucleotides in length, were designed to screen for all possible heterozygous germ-line mutations in the 9.17-kb coding region of the ATM gene. A strategy for rapidly developing multiexon PCR amplification protocols in DNA chip-based hybridization Analysis was devised and implemented in preparing target for the 62 ATM coding exons. Improved algorithms for interpreting data from two-color experiments, where reference and test samples are cohybridized to the arrays, were developed. In a blinded study, 17 of 18 distinct heterozygous and 8 of 8 distinct homozygous sequence variants in the assayed region were detected accurately along with five false-positive calls while scanning >200 kb in 22 genomic DNA samples. Of eight heterozygous sequence changes found in more than one sample, six were detected in all cases. Five previously unreported sequence changes, not found by other Mutational scanning methodologies on these same samples, were detected that led to either amino acid changes or premature truncation of the ATM protein. DNA chip-based assays should play a valuable role in high throughput sequence Analysis of complex genes.
Goran Akerstrom - One of the best experts on this subject based on the ideXlab platform.
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Mutational Analysis of p27 cdkn1b and p18 cdkn2c in sporadic pancreatic endocrine tumors argues against tumor suppressor function
Neoplasia, 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
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Mutational Analysis of p27 (CDKN1B) and p18 (CDKN2C) in sporadic pancreatic endocrine tumors argues against tumor-suppressor function.
Neoplasia (New York N.Y.), 2007Co-Authors: Daniel Lindberg, Goran Akerstrom, Gunnar WestinAbstract:Pancreatic endocrine tumors (PETs) arise sporadically or are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. About 90% of patients with familial MEN1 display detectable MEN1 gene (menin) mutations. The cyclin-dependent kinase inhibitor p27 (CDKN1B) is a downstream target of menin and has been recently shown to be responsible for the multiple endocrine neoplasia-like syndrome in rats, where affected animals develop multiple tumors and hyperplasia in endocrine tissues, including the pancreatic islets of Langerhans. A germline nonsense truncation mutation of p27 has been recently described in a suspected MEN1 family without MEN1 mutation, raising the possibility that p27 mutation could be responsible for MEN1 phenotype. Somatic MEN1 mutations occur at low frequency in sporadic PETs; here, we subjected p27 to Mutational Analysis in 27 sporadic PETs. As an additional menin target, Analysis of the p18 (CDKN2C) gene was included. In the p27 gene, one common polymorphism (V109G) and one novel polymorphism (g/a) in the noncoding part of exon 2 were identified. Three known polymorphisms were found in the p18 gene. These data suggest that p27 and p18 are unlikely to present classic tumor-suppressor genes in sporadic PETs.
