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Clinics in Laboratory Medicine Sep 2021Lymphoblastic leukemias/lymphomas are predominantly diseases of childhood, where they represent almost all acute leukemias; however, they are also encountered with... (Review)
Review
Lymphoblastic leukemias/lymphomas are predominantly diseases of childhood, where they represent almost all acute leukemias; however, they are also encountered with significant frequency in the adult population. These neoplastic processes can be of B-cell or T-cell derivation and are composed of immature precursors of either lineage. The classification of B-lymphoblastic neoplasms relies predominantly on genetic and molecular findings, whereas the same is not true for those of T-lymphoid origin. Many of these recurrent cytogenetic abnormalities have important prognostic and therapeutic implications.
Topics: B-Lymphocytes; Chromosome Aberrations; Humans; Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 34304772
DOI: 10.1016/j.cll.2021.04.003 -
Molecular Cell Mar 2023Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a... (Review)
Review
Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.
Topics: Mitochondrial Proteins; Mitochondria; Mitochondrial Membranes; Carrier Proteins; Protein Transport; Protein Precursors; Mitochondrial Membrane Transport Proteins
PubMed: 36931257
DOI: 10.1016/j.molcel.2023.02.020 -
International Journal of Molecular... Dec 2022Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to... (Review)
Review
Amyloidoses are a group of diseases associated with deposits of amyloid fibrils in different tissues. So far, 36 different types of amyloidosis are known, each due to the misfolding and accumulation of a specific protein. Amyloid deposits can be found in several organs, including the heart, brain, kidneys, and spleen, and can affect single or multiple organs. Generally, amyloid-forming proteins become prone to aggregate due to genetic mutations, acquired environmental factors, excessive concentration, or post-translational modifications. Interestingly, amyloid aggregates are often composed of proteolytic fragments, derived from the degradation of precursor proteins by yet unidentified proteases, which display higher amyloidogenic tendency compared to precursor proteins, thus representing an important mechanism in the onset of amyloid-based diseases. In the present review, we summarize the current knowledge on the proteolytic susceptibility of three of the main human amyloidogenic proteins, i.e., transthyretin, β-amyloid precursor protein, and α-synuclein, in the onset of amyloidosis. We also highlight the role that proteolytic enzymes can play in the crosstalk between intestinal inflammation and amyloid-based diseases.
Topics: Humans; Proteolysis; Amyloidosis; Amyloid; Amyloid beta-Protein Precursor; Protein Precursors; Prealbumin; Peptide Hydrolases
PubMed: 36614141
DOI: 10.3390/ijms24010699 -
The FEBS Journal Jul 2022Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily... (Review)
Review
Coordination of transcription and processing of RNA is a basic principle in regulation of gene expression in eukaryotes. In the case of mRNA, coordination is primarily founded on a co-transcriptional processing mechanism by which a nascent precursor mRNA undergoes maturation via cleavage and modification by the transcription machinery. A similar mechanism controls the biosynthesis of rRNA. However, the coordination of transcription and processing of tRNA, a rather short transcript, remains unknown. Here, we present a model for high molecular weight initiation complexes of human RNA polymerase III that assemble on tRNA genes and process precursor transcripts to mature forms. These multifunctional initiation complexes may support co-transcriptional processing, such as the removal of the 5' leader of precursor tRNA by RNase P. Based on this model, maturation of tRNA is predetermined prior to transcription initiation.
Topics: Humans; RNA Polymerase III; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; Ribonuclease P; Transcription, Genetic
PubMed: 33929081
DOI: 10.1111/febs.15904 -
Current Opinion in Cell Biology Apr 2022The majority of cellular proteins are targeted to organelles. Cytosolic ribosomes produce these proteins as precursors with cleavable or non-cleavable targeting... (Review)
Review
The majority of cellular proteins are targeted to organelles. Cytosolic ribosomes produce these proteins as precursors with cleavable or non-cleavable targeting sequences that direct them to receptor proteins on the organelle surface. Multiple targeting factors ensure cellular sorting of the precursor proteins. In co-translational protein import, the ribosome-nascent chain complex is transported to the organellar protein translocase to couple protein synthesis and protein import. In post-translational mode, targeting factors like molecular chaperones guide the precursor proteins from ribosomes to the cell organelle. Defects in protein targeting and import cause mistargeting of proteins to different cellular compartments and challenge the balance of cellular proteostasis. Specific dislocases and degradation machineries remove such mislocalized proteins from the membrane to allow retargeting or their proteasomal turnover. In this review, we discuss targeting and quality control factors that ensure fidelity of protein targeting to mitochondria.
Topics: Mitochondria; Molecular Chaperones; Organelles; Protein Precursors; Protein Transport; Ribosomes
PubMed: 35306313
DOI: 10.1016/j.ceb.2022.02.005 -
The Journal of Investigative Dermatology Jan 2023Deciphering the pathways that regulate human epidermal precursor cell fate is necessary for future developments in skin repair and graft bioengineering. Among them,...
Deciphering the pathways that regulate human epidermal precursor cell fate is necessary for future developments in skin repair and graft bioengineering. Among them, characterization of pathways regulating the keratinocyte (KC) precursor immaturity versus differentiation balance is required for improving the efficiency of KC precursor ex vivo expansion. In this study, we show that the transcription factor MXD4/MAD4 is expressed at a higher level in quiescent KC stem/progenitor cells located in the basal layer of human epidermis than in cycling progenitors. In holoclone KCs, stable short hairpin-RNA‒mediated decreased expression of MXD4/MAD4 increases MYC expression, whose modulation increases the proliferation of KC precursors and maintenance of their clonogenic potential and preserves the functionality of these precursors in three-dimensional epidermis organoid generation. Altogether, these results characterize MXD4/MAD4 as a major piece of the stemness puzzle in the human epidermis KC lineage and pinpoint an original avenue for ex vivo expansion of human KC precursors.
Topics: Humans; Cell Differentiation; Epidermal Cells; Epidermis; Keratinocytes; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36007550
DOI: 10.1016/j.jid.2022.07.020 -
The FEBS Journal Nov 2022Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the... (Review)
Review
Most chloroplast proteins are nucleus-encoded, translated on cytoplasmic ribosomes as precursor proteins, and imported into chloroplasts through TOC and TIC, the translocons of the outer and inner chloroplast envelope membranes. While the composition of the TOC complex is well established, there is still some controversy about the importance of a recently identified TIC complex consisting of Tic20, Tic214, Tic100, and Tic56. TOC and TIC form a supercomplex with a protein channel at the junction of the outer and inner envelope membranes through which preproteins are pulled into the stroma by the ATP-powered Ycf2 complex consisting of several FtsH-like ATPases and/or by chloroplast Hsp proteins. Several components of the TOC/TIC system are moonlighting proteins with additional roles in chloroplast gene expression and metabolism. Chaperones and co-chaperones, associated with TOC and TIC on the cytoplasmic and stromal side of the chloroplast envelope, participate in the unfolding and folding of the precursor proteins and act together with the ubiquitin-proteasome system in protein quality control. Chloroplast protein import is also intimately linked with retrograde signaling, revealing altogether an unsuspected complexity in the regulation of this process.
Topics: Plant Proteins; Chloroplasts; Chloroplast Proteins; Protein Transport; Molecular Chaperones; Protein Precursors
PubMed: 35472255
DOI: 10.1111/febs.16464 -
Journal of Applied Behavior Analysis Jul 2019Researchers have developed precursor functional analyses to provide an alternative, and presumably safer, format for functional analysis of severe problem behavior. When... (Review)
Review
Researchers have developed precursor functional analyses to provide an alternative, and presumably safer, format for functional analysis of severe problem behavior. When researchers use functional analysis contingencies for precursor behaviors, it is possible to infer functional characteristics about severe problem behaviors based on patterns of less severe precursor behaviors, permitting practitioners to complete the assessment with less risk to clients, practitioners, or others. The current paper discusses recent advances in the development and validation of precursor identification, and offers suggestions and future directions for investigating and implementing precursor functional analyses. We propose a decision-making model, in which practitioners integrate procedures to identify precursors into the functional-analysis process, to expedite the analysis of severe problem behaviors.
Topics: Humans; Models, Psychological; Problem Behavior; Prodromal Symptoms; Reinforcement, Psychology
PubMed: 31049979
DOI: 10.1002/jaba.571 -
Current Opinion in Biotechnology Jun 2021The widely used polyketide pharmaceuticals in medicine and agriculture are mainly produced by Streptomyces species. These compounds, as secondary metabolites, are not... (Review)
Review
The widely used polyketide pharmaceuticals in medicine and agriculture are mainly produced by Streptomyces species. These compounds, as secondary metabolites, are not involved in essential cellular processes and are usually produced during the stationary phase of fermentation. Consequently, their yields and productivities are often low and frequently limited by the availability of the precursors. The precursor pathways, therefore, are key entities for synthetic biology-driven design and optimization. We discuss recent advances in precursor engineering, in both Streptomyces and other bacteria, focusing on the diverse native and heterologous precursor pathways that could be rewired for polyketide titer improvement. We also highlight the coordination of other required factors to direct the precursors towards polyketide biosynthesis. The precursor-supply enhancement tools and strategies covered in this review will facilitate the design and construction of synthetic Streptomyces 'cell-factories' for efficient polyketide production.
Topics: Pharmaceutical Preparations; Polyketides; Secondary Metabolism; Streptomyces; Synthetic Biology
PubMed: 33316577
DOI: 10.1016/j.copbio.2020.11.006 -
The Biochemical Journal Aug 2021Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of... (Review)
Review
Mitochondria import about 1000 proteins that are produced as precursors on cytosolic ribosomes. Defects in mitochondrial protein import result in the accumulation of non-imported precursor proteins and proteotoxic stress. The cell is equipped with different quality control mechanisms to monitor protein transport into mitochondria. First, molecular chaperones guide unfolded proteins to mitochondria and deliver non-imported proteins to proteasomal degradation. Second, quality control factors remove translocation stalled precursor proteins from protein translocases. Third, protein translocases monitor protein sorting to mitochondrial subcompartments. Fourth, AAA proteases of the mitochondrial subcompartments remove mislocalized or unassembled proteins. Finally, impaired efficiency of protein transport is an important sensor for mitochondrial dysfunction and causes the induction of cellular stress responses, which could eventually result in the removal of the defective mitochondria by mitophagy. In this review, we summarize our current understanding of quality control mechanisms that govern mitochondrial protein transport.
Topics: Animals; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitophagy; Models, Biological; Protein Precursors; Protein Transport; Quality Control
PubMed: 34436539
DOI: 10.1042/BCJ20190584