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PubMed2002

LIM proteins: association with the actin cytoskeleton.

The LIM domain is an evolutionary conserved double-zinc finger motif found in a variety of proteins exhibiting diverse biological roles. LIM domains have been observed to act as modular protein-binding interfaces mediating protein-protein interactions in the cytoplasm and the nucleus. Interaction of LIM domains with specific protein partners is now known to influence its subcellular localization and activity; however, no single binding motif has been identified as a common target for LIM domains. Several LIM domain-containing proteins associated with the actin cytoskeleton have been identified, playing a role in signal transduction and organization of the actin filaments during various cellular processes.

Actins↗
PubMed2002

Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript.

The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension on both functional and genetic grounds. By targeting the epithelial sodium channel (ENaC) for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron. Genetic linkage has been reported to a region of chromosome 18q harboring the gene, with phenotypes that include a rare orthostatic hypotension disorder, essential hypertension, and postural change in systolic blood pressure. A systematic search for genetic polymorphisms by resequencing exons and intron boundaries in 48 Caucasians yielded 38 variants. Among these, variant 13 is common, with either G (70%) or A (30%) as the last nucleotide of a putative exon 1. This mutation could affect the generation of a previously unrecognized splice isoform. In subsequent experiments, (1) we confirmed the presence of this putative isoform in both kidney and adrenals; (2) we established that variant 13-A leads to the systematic use of an alternative splice site, generating a transcript encoding a nonfunctional protein; and (3) we demonstrated differences in tissue-specific expression of the novel isoform relative to its previously reported counterpart. Variant 13-A precludes the formation of a transcript encoding a full-length Ca2+-dependent lipid-binding (C2) domain with very high evolutionary conservation among NEDD4L orthologs. A similar C2 domain in the paralogous NEDD4 gene plays a significant role in the transfer of its product to the apical membrane of epithelial cells. Differential function of NEDD4L isoforms could prove significant in blood pressure regulation through an effect on ENaC-dependent sodium reabsorption.

Alternative Splicing↗
PubMed2005

Increased phosphorylation and decreased level of IkappaBalpha during aging in rat liver.

Nuclear factor kappa B (NFkappaB) is an evolutionary conserved transcription factor, which coordinates various metabolic processes triggered by innate and adaptive immune responses. Supakar et al. (J. Biol. Chem. 270: 837-842, 1995) had reported a 10-fold increase in DNA binding activity of NFkappaB in liver of old rats. In this study, we have analyzed the changes in the level of NFkappaB, inhibitor of NFkappaB (IkappaBalpha), phosphorylated-IkappaBalpha (p-IkappaBalpha) and IkappaB kinase (IKK) in rat liver during aging by reverse transcription polymerase chain reaction and/or western blotting. Here we demonstrate that there is an age-dependent increase in the level of p-IkappaBalpha with concomitant decrease in the level of IkappaBalpha, which may be correlated with increased inflammation, oxidative stress and higher level of activated NFkappaB in rat liver in old age.

Aging↗
PubMed2026

Whole-Genome Deep Learning Predicts Chemotherapy Response in Colorectal Cancer.

Chemotherapy response in colorectal cancer (CRC) exhibits significant heterogeneity, with current clinical predictors failing to capture complex genomic determinants of resistance. We developed a hybrid deep learning framework integrating convolutional neural networks (CNNs) and bidirectional long short-term memory (BiLSTM) networks to analyze whole-genome somatic mutations, evolutionary conservation, chromatin accessibility, and 3D genome architecture in 2,546 TCGA patients. An attention mechanism identified predictive genomic regions. The model achieved an AUC of 0.92 (95% CI: 0.89-0.94) in cross-validation and 0.88 (95% CI: 0.85-0.91) in independent validation, outperforming clinical models (&#x394;AUC = +0.18, p < 0.001). Key predictors included non-coding variants in TP53, KRAS, and PIK3CA regulatory regions. Triple-positive patients (mutations in all 3 regions) had significantly worse progression-free survival (HR = 4.7, p < 0.001). Our framework enables accurate chemotherapy response prediction and reveals novel non-coding resistance mechanisms, advancing precision oncology in CRC.

Humans↗
PubMed2005

Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer.

X-ray repair cross-complementing 1 (XRCC1) gene encodes for a scaffolding protein, which plays an important role in base excision DNA repair by bringing together DNA polymerase beta, DNA ligase III and poly(ADP-Ribose) polymerase (PARP) at the site of DNA damage. Three polymorphisms of the XRCC1 gene at codons 194, 280 and 399 leading to amino acid changes at evolutionary conserved regions are found to alter the efficiency of the resulting protein and may therefore constitute potential breast cancer risk. In the present study we sought to determine whether these genetic variants of the XRCC1 gene was associated with any increased risk of breast cancer among the South Indian women in a hospital based case control study using PCR-RFLP and DNA sequencing techniques. Our data showed a positive association between the polymorphisms of codons 194 (OR = 1.98, 95% CI = 1.13-3.48 for Trp allele) and 399 (OR = 2.14, 95% CI = 1.29-3.58 for Gln allele) and breast cancer risk. However, XRCC1 codon 280 genotype analysis showed no evidence for an association with increased risk of breast cancer. A combined analysis of the effect of XRCC1 codon 194 and 399 revealed the highest risk (OR = 3.64, 95% CI = 1.57-8.46) for carriers of the polymorphic alleles in both these codons. In conclusion, the present study suggested involvement of XRCC1 codon 194 and 399 polymorphisms in the genetic predisposition to breast cancer among South Indian women. Our preliminary results based on the analysis of functionally relevant polymorphisms in XRCC1 low penetrance gene may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer.

Breast Neoplasms↗
PubMed2007

A missense germline mutation in exon 7 of the MSH2 gene in a HNPCC family from center-Italy.

INTRODUCTION: Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inherited disease predisposing to the development of colorectal cancers and several other malignancies (endometrium, ovaries, stomach, small bowel, hepatobiliary and urinary tract). HNPCC is caused by germline mutations in any of the MisMatch Repair (MMR) genes. Mutations in MLH1 and MSH2 account for almost 90% of all identified ones. About 15% of mutations identified in MSH2 are missense ones. PATIENTS AND METHODS: We studied one family, fulfilling Amsterdam II criteria, referred to our Center for genetic counselling. The proband, and some of her relatives, have been investigated for microsatellite instability (MSI), immunohistochemical MMR protein staining and by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: All patients carried the same novel MSH2 germline missense mutation (R359S) in exon 7, which determines the substitution of an Arginine, which is a basic amino acid, with a polar Serine residue (R359S). The mutation was associated with lack of expression of MSH2 protein and high microsatellite instability in tumour tissues. The same mutation has been detected in one healthy relative. CONCLUSIONS: The mutation here reported shows a high correlation with phenotype. The mutation is located in an evolutionary conserved domain. Taken together, our findings suggest evidence that the amino acid substitution can be interpreted as pathogenetic.

Adenocarcinoma↗
PubMed2006

DNA mismatch repair and Lynch syndrome.

The evolutionary conserved mismatch repair proteins correct a wide range of DNA replication errors. Their importance as guardians of genetic integrity is reflected by the tremendous decrease of replication fidelity (two to three orders of magnitude) conferred by their loss. Germline mutations in mismatch repair genes, predominantly MSH2 and MLH1, have been found to underlie the Lynch syndrome (also called hereditary non-polyposis colorectal cancer, HNPCC), a hereditary predisposition for cancer. Lynch syndrome affects predominantly the colon and accounts for 2-5% of all colon cancer cases. During more than 30 years of biochemical, crystallographic and clinical research, deep insight has been achieved in the function of mismatch repair and the diseases that are associated with its loss. We review the biochemistry of mismatch repair and also introduce the clinical, diagnostic and genetic aspects of Lynch syndrome.

Adenosine Triphosphatases↗
PubMed2005

Mitochondria and endoplasmic reticulum: the lethal interorganelle cross-talk.

The fundamental contribution of the mitochondria and ER to the decision made on the cell's fate has been increasingly recognized. This progress has illuminated the need for the mechanisms these organelles use to initiate and to propagate apoptotic signals. The toolbox of the mitochondria and ER is evolutionary conserved, overlapping and complementary. Furthermore, mitochondria are often closely associated with the ER providing the conditions for a local and privileged communication between the two organelles. The present review is concerned with the spatially and temporally coordinated utilization of Bcl-2 family proteins and Ca(2+) by the mitochondria and ER to control the membrane permeabilization in the mitochondria and to regulate Ca(2+) distribution and the activity of apoptotic proteins in the ER. The apoptotic means of the mitochondria and ER will eventually come together to control the dismantling of the cell by the caspases and other enzymes.

Animals↗
PubMed2006

Novel frequenin-modulated Ca2+-signaling membrane guanylate cyclase (ROS-GC) transduction pathway in bovine hippocampus.

Frequenin is a member of the neuronal Ca(2+) sensor protein family, implicated in being the modulator of the neurotransmitter release, potassium channels, phosphatidylinositol signaling pathway and the Ca(2+)-dependent exocytosis of dense-core granules in the PC12 cells. Frequenin exhibits these biological activities through its Ca(2+) myristoyl switch, yet the switch is functionally inactive. These structural and functional traits of frequenin have been derived through the use of recombinant frequenin. In the present study, frequenin (BovFrq) native to the bovine hippocampus has been purified, sequenced for its 9 internal fragments, cloned, and studied. The findings show that structure of the BovFrq is identical to its form present in chicken, rat, mouse and human, indicating its evolutionary conservation. Its Ca(2+) myristoyl switch is active in the hippocampus. And, BovFrq physically interacts and turns on yet undisclosed ONE-GC-like ROS-GC membrane guanylate cyclase transduction machinery in the hippocampal neurons. This makes BovFrq a new Ca(2+)-sensor modulator of a novel ROS-GC transduction machinery. The study demonstrates the presence and mechanistic features of this cyclic GMP signaling pathway in the hippocampal neurons, and also provides one more support for the evolving concept where the Ca(2+)-modulated membrane guanylate cyclase transduction machinery in its variant forms is a central operational component of all neurons.

Amino Acid Sequence↗
PubMed2006

A novel zinc-finger protein ZNF436 suppresses transcriptional activities of AP-1 and SRE.

Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes in cell signal transduction connecting cell-surface receptors to critical regulatory targets within cells and control cell survival, adaptation, and proliferation. Previous studies revealed that zinc finger proteins are involved in the regulation of the MAPK signaling pathways. Here we report the identification and characterization of a novel human zinc finger protein, ZNF436. The cDNA of ZNF436 is 3.8 kb, encoding 470 amino acids in the nucleus. The protein is highly conserved in evolution across different vertebrate species from rat to human. RT-PCR indicates that ZNF436 is expressed in all the human fetal tissues examined, with a high level in brain and heart. Overexpression of pCMV-tag2A-ZNF436 in the COS-7 cells represses the transcriptional activities of SRE and AP-1. These results suggest that ZNF436 is a member of the zinc finger transcription factor family and may act as a negative regulator in gene transcription mediated by the MAPK signaling pathways.

Amino Acid Sequence↗
PubMed2006

The nucleolar protein SURF-6 is essential for viability in mouse NIH/3T3 cells.

SURF-6 is a bona fide nucleolar protein comprising an evolutionary conserved family that extends from human to yeast. The expression of the mammalian SURF-6 has been recently found to be regulated during the cell cycle. In order to determine the importance of SURF-6 in mammalian cells, we applied the Tet-On system to regulate conditionally, in response to tetracycline, the expression of an antisense RNA (asRNA) that targets Surf-6 mRNA in mouse NIH/3T3 cells. Induced Surf-6 asRNA caused an effective depletion of SURF-6 protein resulted in cell death and in an apparent arrest in the G1 phase of the cell cycle. These results provide for the first time evidence that expression of SURF-6 is essential for mammalian cell viability, and suggest that SURF-6 might participate in the progression of cell cycle.

Animals↗
PubMed2004

Fighting geminiviruses by RNAi and vice versa.

Geminiviruses have recently emerged not only as the cause of devastating diseases of important crop plants but also as a tool to study fundamental aspects of RNA interference (RNAi) and virus-induced gene silencing. RNA silencing is an evolutionary conserved mechanism protecting cell from pathogenic RNA and DNA, which is increasingly viewed as an adaptive immune system of plants against viruses. Here we summarize recent developments in the field of geminivirology presented by several leading groups at the Meeting "Gemini2004" (a total of 85 participants from all over the world) with the main focus on the anti-viral strategies that exploit RNAi and related silencing phenomena.

Geminiviridae↗
PubMed2004

Characterization and structural features of a chalcone synthase mutation in a white-flowering line of Matthiola incana R. Br. (Brassicaceae).

For Matthiola incana (Brassicaceae), used as a model system to study biochemical and genetical aspects of anthocyanin biosynthesis, several nearly isogenic colored wild type lines and white-flowering mutant lines are available, each with a specific defect in the genes responsible for anthocyanin production (genes e, f, and g). For gene f supposed to code for chalcone synthase (CHS; EC 2.3.1.74), the key enzyme of the flavonoid/anthocyanin biosynthesis pathway belonging to the group of type III polyketide synthases (PKS), the wild type genomic sequence of M. incana line 04 was determined in comparison to the white-flowering CHS mutant line 18. The type of mutation in the chs gene was characterized as a single nucleotide substitution in a triplet AGG coding for an evolutionary conserved arginine into AGT coding for serine (R72S). Northern blots and RT-PCR demonstrated that the mutated gene is expressed in flower petals. Heterologous expression of the wild type and mutated CHS cDNA in E. Scherichia coli, verified by Western blotting and enzyme assays with various starter molecules, revealed that the mutant protein had no detectable activity, indicating that the strictly conserved arginine residue is essential for the enzymatic reaction. This mutation, which previously was not detected by mutagenic screening, is discussed in the light of structural and functional information on alfalfa CHS and related type III PKS enzymes.

Acyltransferases↗
PubMed1977

Clinical, pathologic, and genetic findings in a case of 46,XY pure gonadal dysgenesis (Swyer's syndrome). II. Presence of H-Y antigen.

Evidence that expression of histocompatibility-Y (H-Y) antigen on human cells is determined by a Y-linked gene is provided by data demonstrating that male subjects with two Y chromosomes have higher antigen levels than male subjects with one Y chromosome. The widespread evolutionary conservation of H-Y antigen and its association with the Y chromosome suggest that the antigen has a specific, crucial function. We surmise that this function is the differentiation of the embryonic gonad into whichever mature gonad, testis or ovary, typifies the heterogametic sex of each species. Of particular interest are individuals whose gonadal sex does not correspond to their somatic genotype. In the present article, we report positive results in the first case of 46,XY pure gonadal dysgenesis (Swyer's syndrome) to be typed for H-Y antigen. This case suggests that the presence of H-Y antigen may not be sufficient to complete masculinization of the embryonic mammalian gonad. Alternatively, a mutant gene may govern expression of a cell surface component which cross reacts with H-Y antigen but which lacks the ability to function in the virilization of the gonad.

Adolescent↗
PubMed1985

Immunological characterization of phosphoprotein phosphatases.

Phosphoprotein phosphatases regulate the biological activities of proteins through their involvement in cyclic phosphorylation/dephosphorylation cascades. A variety of multimeric phosphatases have been isolated and grouped into several classes, termed type 1 and types 2A, 2B, and 2C. To elucidate the relationship between the different phosphoprotein phosphatases, highly purified enzymes from soil amoebae, turkey gizzards, bovine heart and brain, and rabbit skeletal muscle and reticulocytes were tested for immunological antigenic relatedness. Two heterologous antibody preparations were employed for this purpose. One was made against an Acanthamoeba type 2A phosphatase and the other was made to bovine brain phosphatase type 2B (calcineurin, holoenzyme). Specific subunit cross-reactivity was examined by protein blot ("Western") analysis. The antibody to the type 2A phosphatase reacted with the catalytic subunits of every type 2 enzyme tested, including both the catalytic and Ca2+-binding subunits of the Ca2+/calmodulin-dependent type 2B phosphatase (calcineurin), bovine cardiac type 2A phosphatase, and turkey gizzard smooth muscle phosphatase-1 (type 2A1). It did not react with any type 1 phosphatase (catalytic subunit or ATP-Mg-dependent). The antigenic relatedness of calcineurin and the bovine cardiac type 2A phosphatase (Mr 38,000) was demonstrated further by protein blot analysis showing that the anti-calcineurin antibody cross-reacted with both enzymes. The mutual cross-reactivity poses an intriguing problem because these enzymes are so different in their molecular structures and modes of regulation. The degree of evolutionary conservation exhibited by the antigenic cross-reactivity of the type 2 enzymes from a broad range of species and tissues suggests a strong selective pressure on maintaining one or more features of these important regulatory enzymes.

Animals↗
PubMed1986

Secondary structure predictions of human plasminogen and the bovine prothrombin kringle loops.

Secondary structural predictions, based upon the statistical methodology of Chou and Fasman, for the kringle loops of human plasminogen and bovine prothrombin suggest a "winding staircase" pattern of beta-turns, spaced by short regions of ordered and coil structures. Analysis of the predicted structures of the regions containing the two His (113 and 387) and Asp (136 and 410) residues in plasminogen kringles 1 and 4, which have been found to be important in binding the ligand, epsilon-aminocaproic acid, shows that all are localized at the same positions on beta-turns. In addition, both of the two Asp residues occur at the end of homologous nonapeptide regions common to all of the five human plasminogen and two bovine prothrombin kringles, indicating evolutionary conservation to preserve biologically critical conformations. Examination of the protein conformation in the region of Asn288, the residue which is glycosylated in one of the two circulating variants of human plasminogen, shows that it most likely exists in a position which may present topographical hindrance to post-translational attachment of carbohydrate, thus, possibly, explaining the incomplete glycosylation of human plasminogen with complex-type carbohydrate.

Amino Acid Sequence↗
PubMed1992

Characterization and partial purification of an insulinase from Neurospora crassa.

An insulin-binding metal- and thiol-dependent proteinase has been purified 1491-fold from high speed cytosolic fractions of the fungus Neurospora crassa. This enzyme resembles insulin-degrading enzymes (insulinases) present in mammalian cells and in Drosophila melanogaster in the following ways: (i) it degrades radiolabeled insulin with a specificity similar to that of rat muscle insulinase, as demonstrated by HPLC analysis of the degradation products; (ii) it is inhibited by bacitracin, EDTA, 1,10-phenanthroline, and the sulfhydryl-reactive compounds N-ethylmaleimide and p-chloromercuribenzoate, but not by inhibitors of serine proteases or by lysosomal protease inhibitors. Cross-linking with 125I-insulin labels a band of ca. 120 kDa, and several smaller bands which may represent degradation products. The N. crassa insulinase is stimulated by Mn2+ and strongly inhibited by Zn2+; Mn2+ can also reactivate the enzyme after inhibition by EDTA, but Zn2+ is ineffective. The N. crassa protein differs in this regard from mammalian and insect insulinases which are generally activated by both Mn2+ and Zn2+. This finding extends the apparent evolutionary conservation of these metal- and thiol-dependent proteases into the microbial realm.

Cations, Divalent↗