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

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

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

OBJECTIVETo demonstrate the expression of proteolysis induce factor(PIF) in the gastrointestinal(GI) cancer cachexia patients and evaluate its role in cancer cachexia.

METHODSExamination of PIF was performed in urine samples from 28 GI cancer cachexia patients, 13 GI cancer patients without cachexia, and 12 weight loss patients with benign disease. PIF was added to the mice cultured C2C12 muscle cells, then the protein kinase B(Akt) phosphorylation and morphological change were measured.

RESULTSThe positive rate of PIF in urine of 28 cancer cachexia patients was 53.6%(15/28). In the other two groups, no positive result was detected. PIF could successfully induce Akt phosphorylation, cell atrophy, metamorphosis, and death. The peak of this phosphorylation could be detected after half an hour of the initiation of PIF at a concentration of 4 nmol/L.

CONCLUSIONSPIF is specifically and highly expressed in GI cancer cachexia patients' urine. PIF can induce cancer cachexia possibly by activating Akt phosphorylation and inducing downstream proteolysis.

Animals ; Cachexia ; etiology ; metabolism ; Cell Line ; Gastrointestinal Neoplasms ; complications ; Humans ; Mice ; Proteoglycans ; Proteolysis

Voltage gated calcium channels (VGCCs) are multi-subunit membrane proteins present in a variety of tissues and control many essential physiological processes. Due to their vital importance, VGCCs are regulated by a myriad of proteins and signaling pathways. Here we review the literature on the regulation of VGCCs by proteolysis of the pore-forming α1 subunit, Ca(v)α(1). This form of regulation modulates channel function and degradation and affects cellular gene expression and excitability. L-type Ca(2+) channels are proteolyzed in two ways, depending on tissue localization. In the heart and skeletal muscle, the distal C-terminus of Ca(v)α(1) is cleaved and acts as an autoinhibitor when it reassociates with the proximal C-terminus. Relief of this autoinhibition underlies the β-adrenergic stimulation-induced enhancement of cardiac and skeletal muscle calcium currents, part of the "fight or flight" response. Proteolysis of the distal C-terminus of L-type channels also occurs in the brain and is probably catalyzed by a calpain-like protease. In some brain regions, the entire C-terminus of L-type Ca(2+) channels can be cleaved by an unknown protease and translocates to the nucleus acting as a transcription factor. The distal C-terminus of P/Q-channel Ca(v)α(1) is also proteolyzed and translocates to the nucleus. Truncated forms of the PQ-channel Ca(v)α(1) are produced by many disease-causing mutations and interfere with the function of full-length channels. Truncated forms of N-type channel Ca(v)α(1), generated by mutagenesis, affect the expression of full-length channels. New forms of proteolysis of VGCC subunits remain to be discovered and may represent a fruitful area of VGCC research.
Animals ; Calcium Channels, L-Type ; metabolism ; Calcium Signaling ; Humans ; Muscle, Skeletal ; physiology ; Proteolysis