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PubMed2003

Epigenetic changes: potential therapeutic targets.

Recent advances in human genome research have resulted in novel approaches for the identification of epigenetic modifications associated with cancer. Modulators of DNA methylation and chromatin structure have a dramatic effect on gene expression, cellular proliferation, differentiation, and apoptosis. Molecular pathways regulating epigenetic events that occur during tumorigenesis have been exploited as new targets for therapeutic intervention. Clinical studies exploring the effectiveness of therapeutic agents targeting DNA methylation and acetylation of histones have yielded promising results. Molecular profiles of epigenetic alterations in cancer cells could allow better stratification of patients who may show responsiveness to specific treatments.

Acetylation↗

PubMed2006

[Rationale of antiangiogenic therapy].

Vascularization of cancer is a complex and heterogenous process where neoangiogenesis by sprouting is only one of the possible mechanisms that also include postnatal vasculogenesis, vessel incorporation, intussusceptive microvascular growth, glomeruloid angiogenesis and vascular mimicry. Furthermore, the mechanism of vascularization may also depend on the cancer type and the host tissue as well. Antivascular agents can be divided into angiosuppressive ones (endothelial cell proliferation inhibitors), vascular-targeted agents (microvessel disrupting agents) and anti-hypoxia agents (targeting the molecular pathways responsible for the development of the angiogenic phenotype). Since antivascular therapy is a special form of targeted therapy, it is necessary to apply it in a rational manner to consider the type of vascularization, the molecular background of the angiogenic phenotype, the stage of the disease and the standard anticancer therapy. Whithout such a fine-tuning, antivascular therapies cannot be integrated more successfully into the management of cancer patients.

Angiogenesis Inhibitors↗

PubMed2001

Signaling pathways controlling cell polarity and chemotaxis.

Many important biological processes, including chemotaxis (directional cell movement up a chemoattractant gradient), require a clearly established cell polarity and the ability of the cell to respond to a directional signal. Recent advances using Dictyostelium cells and mammalian leukocytes have provided insights into the biochemical and molecular pathways that control chemotaxis. Phosphoinositide 3-kinase plays a central and possibly pivotal role in establishing and maintaining cell polarity by regulating the subcellular localization and activation of downstream effectors that are essential for regulating cell polarity and proper chemotaxis. This review outlines our present understanding of these pathways.

Actins↗

PubMed2004

Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells.

We previously reported that injury-induced medial vascular smooth muscle cell (VSMC) proliferation and neointima formation in carotid arteries of inducible nitric oxide synthase knockout (iNOS KO) mice were significantly reduced compared with wild type (WT). However, the molecular pathway underlying such differences is not known. In this in vitro study, we discovered that the AP-1/Ref-1/thioredoxin signaling pathway is altered in aortic VSMC from iNOS KO mice, which leads to reduced growth response when compared with aortic VSMC from WT mice. After equal initial seeding, the cell number after 7 days in serum medium was less in iNOS KO cells compared with WT VSMC (1.2 +/- 0.6 x 10(5) vs 3.2 +/- 1.1 x 10(5); p < 0.05). Significantly more iNOS KO cells remained in the G0/G1 phase compared with WT cells after 24-h serum treatment (82.6 +/- 13.7% vs 62.3 +/- 14.6%; p < 0.05) by cell-cycle analysis. Nuclear PCNA expression was also less in the iNOS KO cells, which was not affected by exogenous NO or superoxide. Superoxide generation after 24-h serum stimulation was less in the iNOS KO cells compared with WT cells. After 30-min serum stimulation, AP-1 DNA binding was reduced and a lack of increase in nuclear c-Jun protein was observed in iNOS KO VSMC. RT-PCR analysis confirmed a lack of inducible c-Jun mRNA after serum stimulation in the KO cells. In addition, KO cells had less nuclear reducing factor-1 (Ref-1) and serum-inducible thioredoxin protein expression. Reduced proliferative response of iNOS KO VSMC to serum treatment is associated with altered AP-1 /Ref-1 /thioredoxin pathway activation.

Animals↗

PubMedDate not supplied

Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time.

The major mission of the cell division cycle is a faithful and complete duplication of the genome followed by an equal partitioning of chromosomes to subsequent cell generations. In this review, we discuss the advances in our understanding of how mammalian cells control the fidelity of these fundamental processes when exposed to diverse genotoxic insults. We focus on the most recent insights into the molecular pathways that link the sites of DNA lesions with the cell cycle machinery in specific phases of the cell cycle. We also highlight the potential of a new technology allowing direct visualization of molecular interactions and redistribution of checkpoint proteins in live cell nuclei, and document the emerging significance of live-cell imaging for elucidation of the spatio-temporal organization of the DNA damage response network.

Animals↗

PubMed2026

Genetic diversity and molecular mechanisms in hypertrophic cardiomyopathy: toward personalized therapy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-β (TGF-β) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.

Humans↗

PubMed2005

Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT.

Genetic studies in humans and mice have revealed an important role of the Wnt signaling pathway in the regulation of bone mass, resulting from potent effects on the control of osteoblast progenitor proliferation, commitment, differentiation, and perhaps osteoblast apoptosis. To establish the linkage between Wnts and osteoblast survival and to elucidate the molecular pathways that link the two, we have utilized three cell models: the uncommitted bipotential C2C12 cells, the pre-osteoblastic cell line MC3T3-E1, and bone marrow-derived OB-6 osteoblasts. Serum withdrawal-induced apoptosis was prevented by the canonical Wnts (Wnt3a and Wnt1) and the noncanonical Wnt5a in all cell types. Wnt3a induced LRP5-independent transient phosphorylation and nuclear accumulation of ERKs and phosphorylation of Src and Akt. The anti-apoptotic effect of Wnt3a was abrogated by inhibitors of canonical Wnt signaling, as well as by inhibitors of MEK, Src, phosphatidylinositol 3-kinase (PI3K), or Akt kinases, or by the addition of cycloheximide to the culture medium. Wnt3a-induced phosphorylation of GSK-3beta and downstream activation of beta-catenin-mediated transcription required ERK, PI3K, and Akt signaling. Wnt3a increased the expression of the anti-apoptotic protein Bcl-2 in an ERK-dependent manner. Beta-catenin-mediated transcription was permissive for the anti-apoptotic actions of Wnt1 and Wnt3a but was dispensable for the anti-apoptotic action of Wnt5a. However, Src, ERKs, PI3K, and Akt kinases were required for the anti-apoptotic effects of Wnt5a. These results demonstrate for the first time that Wnt proteins, irrespective of their ability to stimulate canonical Wnt signaling, prolong the survival of osteoblasts and uncommitted osteoblast progenitors via activation of the Src/ERK and PI3K/Akt signaling cascades.

Animals↗

PubMed2005

The nitric oxide signaling pathway in the penis.

It is widely accepted that nitric oxide plays an important role in the biology of the penis, serving most familiarly as the agent responsible for penile erection. Early investigation in the field led to the identification of the signaling function of the molecule in the penis which yields corporal smooth muscle relaxation fundamental for the erectile response. Ongoing study of this molecule and its signaling pathway in erectile tissue has served to revise and clarify its importance. Current information conveys the prerequisite of the nitric oxide signaling pathway for penile erection, the regulatory basis for the generation and actions of nitric oxide in the penis, the diverse roles of its synthetic enzyme isoforms in penile biology, and the interaction between nitric oxide and other molecular pathways operative in the broad context of erection physiology. Insight into these subject areas has therapeutic relevance for pathologic conditions of the penis. The purpose of this review is to highlight the latest areas of investigation related to the science of nitric oxide in the penis, as a gateway for considering novel therapeutic strategies for erectile disorders now and in the future.

Humans↗

PubMed2001

Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells.

FasL and TNF-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induce apoptosis by binding to their death domain containing receptors. In the present study we have utilized a panel of seven cell lines derived from human malignant gliomas to characterize molecular pathways through which FasL and TRAIL induce apoptosis in sensitive glioma cells and the mechanisms of resistance in cell lines which survive the death stimuli. Our findings indicate that FADD and Caspase-8 are essential for FasL and TRAIL mediated apoptosis in glioma cells. One sensitive cell line (D270) can be protected from FasL and TRAIL induced death by anti-apoptotic Bcl-2 family members while another (D645) cannot, implying that these lines may represent glioma examples of type II and type I cells respectively. For the first time we demonstrate resistance to FasL but not to TRAIL within the one glioma cell line. Furthermore, we report distinct mechanisms of resistance within different glioma lines, including downregulation of Caspase-8 in U373MG. Cycloheximide sensitized four of the resistant cell lines suggesting the presence of labile inhibitors. None of the known apoptosis inhibitors examined accounted for the observed resistance, suggesting novel inhibitors may exist in glioma cells.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Pathways regulating Na+/Ca2+ exchanger expression in the heart.

The Na(+)/Ca(2+) exchanger (NCX1) is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. Following pressure overload, activation of MAPKs coincides with the kinetics of NCX1 gene upregulation in adult cardiocytes. Using adenoviral gene delivery, we begin to identify the molecular pathways responsible for upregulation of the exchanger gene. Inhibition of ERK with the MEK inhibitor UO126, the ERK protein phosphatase MKP-3, inhibited ERK activation, but only inhibited alpha-adrenergic-induced NCX1 upregulation by 30%. Overexpression of DN-JNK lowered basal NCX1 expression. Overexpression of activated MKK-3 was sufficient for alpha-adrenergic-stimulated upregulation of the reporter gene. Together, this data indicates that (1) JNK mediates basal cardiac expression of the NCX1 gene, (2) ERK and p38 play a role in alpha-adrenergic-stimulated NCX1 upregulation, and (3) p38 activation alone is sufficient for NCX1 upregulation.

5' Untranslated Regions↗

PubMed2005

The pro-apoptotic activity of a vertebrate Bar-like homeobox gene plays a key role in patterning the Xenopus neural plate by limiting the number of chordin- and shh-expressing cells.

Targeted disruption of effectors molecules of the apoptotic pathway have demonstrated the occurrence and magnitude of early programmed cell death (EPCD), a form of apoptosis that affects proliferating and newly differentiated cells in vertebrates, and most dramatically cells of the central nervous system (CNS). Little is known about the molecular pathways controlling apoptosis at these early developmental stages, as the roles of EPCD during patterning of the developing nervous system. We describe a new function, in Xenopus neurodevelopment, for a highly conserved homeodomain protein Barhl2. Barhl2 promotes apoptosis in the Xenopus neuroectoderm and mesoderm, acting as a transcriptional repressor, through a mechanism that cannot be attributed to an unspecific cellular stress response. We show that the pro-apoptotic activity of Barhl2 is essential during normal neural plate formation as it limits the number of chordin- and Xshh-expressing cells in the prospective notochord and floorplate, which act as organizing centers. Our findings show that Barhl2 is part of a pathway regulating EPCD. They also provide evidence that apoptosis plays an important role in regulating the size of organizing centers.

Amino Acid Sequence↗

PubMed1999

Muscular dystrophies: alterations in a limited number of cellular pathways?

Identification of new genes involved in muscle disorders has dramatically changed the traditional clinical classification of the large and heterogeneous group of the muscular dystrophies. Results obtained in recent years by positional candidate cloning have demonstrated the role of the sarcolemma and of the nuclear envelope in normal muscle function and have elucidated molecular pathways perturbed by mutations that lead to muscular dystrophy.

Caveolin 3↗

PubMed1998

Reconstruction of amino acid biosynthesis pathways from the complete genome sequence.

The complete genome sequence of an organism contains information that has not been fully utilized in the current prediction methods of gene functions, which are based on piece-by-piece similarity searches of individual genes. We present here a method that utilizes a higher level information of molecular pathways to reconstruct a complete functional unit from a set of genes. Specifically, a genome-by-genome comparison is first made for identifying enzyme genes and assigning EC numbers, which is followed by the reconstruction of selected portions of the metabolic pathways by use of the reference biochemical knowledge. The completeness of the reconstructed pathway is an indicator of the correctness of the initial gene function assignment. This feature has become possible because of our efforts to computerize the current knowledge of metabolic pathways under the KEGG project. We found that the biosynthesis pathways of all 20 amino acids were completely reconstructed in Escherichia coli, Haemophilus influenzae, and Bacillus subtilis, and probably in Synechocystis and Saccharomyces cerevisiae as well, although it was necessary to assume wider substrate specificity for aspartate aminotransferases.

Amino Acids↗

PubMed2000

Apoptotic photoreceptor death in the rhodopsin knockout mouse in the presence and absence of c-fos.

A combined total of approximately 100 mutations have been encountered within the rhodopsin gene in retinitis pigmentosa (RP) and congenital night blindness. Mice carrying a targeted disruption of the rhodopsin gene phenotypically mimic RP, losing their photoreceptors over a period of 3 months and having no recordable rod electroretinogram. These animals will serve as a model for both recessive and dominant disease (in the latter case, the presence of normal and mutant human rod opsin transgenes on the murine Rho(-/-)background). Precise knowledge of apoptotic photoreceptor cell death, together with factors which may influence apoptosis will be required for optimum utility of Rho(-/-)mice as a model for therapeutic genetic intervention. A peak phase of apoptosis of the photoreceptors of Rho(-/-)mice was shown to occur at 24 days post-birth. The extent of apoptosis appeared to be similar, irrespective of whether or not the rod opsin knockout was present on a c-fos(+/+)or c-fos(-/-)genetic background, the latter known to favor survival of photoreceptors following exposure of mouse retinas to excessive light. These data clearly support the existence in animals of distinct apoptotic pathways in light-induced, as opposed to mutation-induced apoptosis, and together with similar observations recently reported in studies of the naturally occurring rd mouse, may assist in focusing future research on precisely defining the distinct molecular pathways giving rise to such dichotomy.

Animals↗

PubMed2004

The signals and pathways activating cellular senescence.

Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. Cellular senescence is thought to play an important role in tumor suppression and to contribute to organismal aging, but a detailed description of its physiologic occurrence in vivo is lacking. Recent studies have provided important insights regarding the manner by which different stresses and stimuli activate the signaling pathways leading to senescence. These studies reveal that a population of growing cells may suffer from a combination of different physiologic stresses acting simultaneously. The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence. Here we review recent advances in our understanding of the stimuli that trigger senescence, the molecular pathways activated by these stimuli, and the manner by which these signals determine the entry of a population of cells into senescence.

Cellular Senescence↗

PubMed1998

Dismantling in cell death: molecular mechanisms and relationship to caspase activation.

The notion of a cell death programme was introduced in view of the reproducibility of its occurrence in time and space (e.g. in the developing embryo) and of its genetic determination. Programmed cell death can be schematically subdivided into three steps: a signalling phase, an execution phase and a dismantling phase. This review focuses on the latter. Apoptosis is the most studied form of dismantling of animal cells. The molecular pathways leading to certain apoptotic lesions appear to be dependent on the proteolytic activity of caspases. Death itself can, however, be caspase-independent. Also, non-apoptotic forms of cell death exist, even in animal cells; their molecular bases are still unknown. The relationship between cell death, apoptosis and caspases is discussed.

Animals↗

PubMed2006

Lack of Rb and p53 delays cerebellar development and predisposes to large cell anaplastic medulloblastoma through amplification of N-Myc and Ptch2.

Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19(ARF), p21, or ATM.

Animals↗

PubMed2026

Decoding protein signatures and protein interactions in oral potentially malignant disorders: a systematic review and network analysis.

BACKGROUND: Proteomic profiling offers thorough insights into protein structure and function, as well as it acts as an essential approach for analyzing molecular changes at the tissue level. However, because of the proteome's diversity and dynamic nature, biomarker discovery remains challenging. By combining proteomics with bioinformatics, the level of understanding in relation to molecular interactions and disease processes can be improved. Through an integrative approach, few limitations can be addressed, thereby promoting proteomic profiling for the discovery of new therapeutic targets and novel biomarkers for a variety of disorders. AIM: To identify differentially expressed protein markers and their key molecular pathways associated with Oral Potentially Malignant Disorders. METHODS: Systematic Review was conducted following the PRISMA guidelines and the protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration ID number CRD42024557545. A comprehensive literature review was performed using electronic databases, yielding 12,797, studies from which 15 eligible articles were selected. The Newcastle-Ottawa Scale was used to assess the risk of bias. Vote counting was performed to identify proteins reported in more than one study. A bipartite network was constructed using Cytoscape to identify shared and disease-specific protein markers. Lesion-wise protein-protein interaction networks were generated using STRING and analysed in Cytoscape to identify highly interconnected hub proteins, and pathway enrichment analysis for these hubs was performed using Reactome. RESULTS: A total of fifteen studies (Leukoplakia (LK) - n = 1, Proliferative Verrucous Leukoplakia (PVL) - n = 2, Oral Submucous Fibrosis (OSMF) - n = 7, and Oral Lichen Planus (OLP) - n = 5) were included. The Newcastle-Ottawa Scale was used to evaluate methodological quality and the quality of studies included in this systematic review was high for 4 articles and moderate in the remaining 11. The most commonly employed technique was mass spectrometry. A total of 318 candidate proteins (LK - 14, PVL - 82, OSMF - 172, and OLP - 50) were identified across the oral potentially malignant disorders. Key markers identified through vote counting included ERO1A, NUCB1, RHOA, and IL36A for PVL; LUM, KRT1, KRT9, ALB, and VIM for OSMF; and ALB, LYZ, HP, HBB, and AMY1A for OLP. The bipartite network showed that OSMF and OLP shared the highest number of proteins, indicating the strongest overlap among lesions. Network analysis further highlighted distinct hub proteins for each lesion: for LK- AMY1A, AMY1B and APOA1; for PVL- CFL1, RHOA and CDC42; for OSMF- HSP90AA1, ENO1 and SERPINA1; and for OLP- HP, B2M, and ORM1. Lesion-specific pathway enrichment revealed that LK was associated with epithelial differentiation, PVL with oncogenic signaling, OSMF with stress-driven fibrosis, and OLP with immune-mediated inflammation. CONCLUSIONS: Proteomic expression offers insights into disease pathogenesis by identifying important molecular changes across OPMDs. However, the majority of biomarkers are still in the exploratory stage due to the considerable variation in lesion types, sample sources, proteomic techniques, and reporting systems. In order to create reliable and clinically applicable biomarkers, future studies should concentrate on combining multi-omics techniques with large-scale, standardized cohorts.

Humans↗