No abstract available.
Insulin* ; Proteolysis*

Small-molecule anticancer drugs inhibited tumor growth based on targeted inhibition of specific proteins, while most of oncogenic proteins are "undruggable". Proteolysis targeting chimeras (PROTAC) is an attractive and general strategy for treating cancer based on targeted degradation of oncogenic proteins. This review briefly describes the peptide-based PTOTAC and small molecule-based PROTAC. Subsequently, we summarize the development of targeted delivery of PROTAC, such as targeting molecule-mediated targeted delivery of PROTAC, nanomaterial-mediated targeted delivery of PROTAC and controllable activation of small-molecular PROTAC prodrug. Such strategies show potential application in improving tumor selectivity, overcoming off-target effect and reducing biotoxicity. At the end, the druggability of PROTAC is prospected.
Humans ; Proteolysis Targeting Chimera ; Nanostructures ; Neoplasms/drug therapy* ; Proteolysis

The BTB (broad-complex, tramtrack, and bric-à-brac) domain is a highly conserved protein interaction motif in eukaryotes. They are widely involved in transcriptional regulation, protein degradation and other processes. Recently, an increasing number of studies have shown that these genes play important roles in plant growth and development, biotic and abiotic stress processes. Here, we summarize the advances of these proteins ubiquitination-mediated development and abiotic stress responses in plants based on the protein structure, which may facilitate the study of this type of gene in plants.
Eukaryota ; Plant Development/genetics* ; Proteolysis ; Ubiquitination

Proteolysis targeting chimera (PROTAC) refers to heterobifunctional small molecules that can simultaneously bind an E3 ubiquitin ligase and a target protein, enabling specific degradation of the target protein with the aid of the ubiquitin proteasome system. At present, most PROTAC drugs are in the clinical trial stage, and the ligands are mainly non-covalent compounds. PROTAC drugs have the advantage of overcoming drug resistance and degrading "undruggable" target proteins, but non-covalent ligands could lead to the hook effect that undermines drug efficacy. With its own advantages, covalent ligands can avoid the occurrence of this phenomenon, which is of great help to the development of PROTAC. This review summarizes the progress in preclinical and clinical research and application of PROTAC molecules targeting three different classes of protein targets, including intranuclear, transmembrane, and cytosolic proteins. We also offer perspective discussions to provide research ideas and references for the future development of PROTAC.
Proteolysis ; Proteolysis Targeting Chimera ; Proteasome Endopeptidase Complex/metabolism* ; Ubiquitin-Protein Ligases/metabolism* ; Proteins/metabolism* ; Ligands

C-termini of proteins often play an important role in various biological processes, such as the transcription and translation from DNA to protein and also participating in various biological regulations. The determination of protein C-terminus is so crucial because it provides not only distinct functional annotation, but also a way to monitor the proteolysis-modified proteins. Based on the biological mass spectrometry, a series of novel methods and technologies were developed both for qualitative and quantitative analyses of protein C-terminus. These methods or technologies can be applied to accurate and effective protein C-terminus profiling, including the sequences and quantitative information of C-termini, which reveals the biological function of C-termini in life's activities and provides a better understanding of the degradation of mature proteins. Combined with our research, this review highlights the improvements in C-terminal proteomics study in the past decades, including the methodologies for recognition and identification of C-terminus, as well as the enrichment strategies for protein C-terminus.
Mass Spectrometry ; Protein Processing, Post-Translational ; Proteins ; chemistry ; Proteolysis ; Proteomics

Ubiquitin-Protein Ligases/metabolism* ; Proteolysis ; Biological Products ; Ligands

The calcium-sensitive neutral protease, calpain, is activated in the basilar artery after subarachnoid hemorrhage. Pathological activation of this proteolytic enzyme has been suggested to contribute to cerebral vasospasm after subarachnoid hemorrhage. The present study was undertaken to evaluate the effects of a newly developed calpain inhibitor, CX-287 on vasospasm. A blind, randomized trial was utilized in which CX-287 was injected intravenously into subarachnoid hemorrhage rabbits. Two days after subarachnoid hemorrhage, animals were sacrificed by perfusion-fixation and cross-sectional areas of the basilar arteries were measured using histological techniques. Expressing the cross-sectional area in the untreated SAH animals as a percentage of control value, it was 38.4+/-5.7%. Basilar artery area of the treatment groups with 1.5mg/kg CX-287(b.i.d. or t.i.d) showed no statistical differences from subarachnoid only group(b.i.d.: 34.7%, t.i.d.: 49.0%). However, the treatment group with 3mg/kg CX-287 showed significant reversal of the subarachnoid hemorrhage-induced constriction(b.i.d.: 73.4%, p<0.0003, t.i.d.: 58.7%, p<0.05). These findings support the important role of calcium activated proteolysis by calpain in the pathophysiology of vasospasm after subarachnoid hemorrhage. Furthermore, these results provide the first demonstration that a calpain inhibitor can inhibit cerebral vasospasm.
Animals ; Basilar Artery ; Calcium ; Calpain* ; Histological Techniques ; Injections, Intravenous ; Proteolysis ; Rabbits ; Subarachnoid Hemorrhage* ; Vasospasm, Intracranial

Antioxidant enzymes levels were determined in monocytes during phorbol myristate acetate (PMA)-induced differentiation. PMA induced the differentiation of a human monocytic leukemia cell line THP-1 into macrophage-like cells as indicated by activity of acid phosphatase and morphological changes. The level of Mn-superoxide dismutase (SOD) was selectively increased in PMA-treated THP-1 cells after one day of culture, while the levels of Cu/Zn-SOD and catalase were progressively decreased by Western blot analysis. In contrast, levels of Cu/Zn-SOD and catalase protein and enzyme activitiy remained unchanged in THP-1 cells after transforming growth factor-p, treatment. Cu/Zn-SOD is oxidatively inactivated by exposure to H,O, which is produced by PMA-treated THP-1 cells, and then the inactivated enzyme undergoes proteolysis and fragmentation as analyzed by radiolabeled method. Thus monocytes have a coordinated system for synthesis and degradation of antioxidant enzymes during PMA-induced differentiation.
Acid Phosphatase ; Blotting, Western ; Catalase ; Cell Line ; Humans ; Leukemia ; Monocytes* ; Proteolysis ; Superoxide Dismutase ; Tetradecanoylphorbol Acetate

Hypoxia is frequently observed in solid tumors and also one of the major obstacles for effective cancer therapies. Cancer cells take advantage of their ability to adapt hypoxia to initiate a special transcriptional program that renders them more aggressive biological behaviors. Hypoxia-inducible factors (HIFs) are the key factors that control hypoxia-inducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. HIFs, mainly HIF-1 and -2, have become potential targets for developing novel cancer therapeutics. This article reviews the updated information in tumor HIF pathways, particularly recent advances in the development of HIF inhibitors. These inhibitors interfere with mRNA expression, protein synthesis, protein degradation and dimerization, DNA binding and transcriptional activity of HIF-1 and -2, or both. Despite efforts in the past two decades, no agents directly inhibiting HIFs have been approved for treating cancer patients. By analyzing results of the published reports, we put the perspectives at the end of the article. The therapeutic efficacy of HIF inhibitors may be improved if more efforts are devoted on developing agents that are able to simultaneously target HIF-1 and -2, increasing the penetrating capacity of HIF inhibitors, and selecting suitable patient subpopulations for clinical trials.
Anoxia ; Dimerization ; DNA ; Humans ; Hypoxia-Inducible Factor 1* ; Proteolysis ; RNA, Messenger

Crystalline nephropathy is a rare yet well-known condition associated with multiple myeloma and other light chain–secreting disorders. Paraproteins that are resistant to proteolysis crystallize within proximal tubular cells and cause light-chain proximal tubulopathy, which presents clinically as Fanconi syndrome. Podocytes are rarely affected, and the crystalline inclusions within podocytes are typically precipitated, yielding significant glomerular proteinuria. Here we report a case of extensive crystalline inclusions primarily within podocytes and proximal tubules that presented only with Fanconi syndrome and renal insufficiency. Despite the presence of extensive crystalline inclusions in podocytes and diffuse foot process effacement, the patient had no clinical evidence suggestive of podocyte injury.
Crystallins* ; Fanconi Syndrome ; Foot ; Humans ; Multiple Myeloma* ; Paraproteins ; Podocytes ; Proteinuria* ; Proteolysis ; Renal Insufficiency