Animals ; Cardiovascular System ; metabolism ; GTPase-Activating Proteins ; metabolism ; Humans ; Nerve Tissue Proteins ; metabolism ; Signal Transduction

GTPase-Activating Proteins ; metabolism ; Humans ; Neoplasms ; metabolism ; rho GTP-Binding Proteins ; metabolism

OBJECTIVE: To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. METHODS: The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. RESULTS: NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. CONCLUSION Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.
Humans ; Neurofibromatosis 1/pathology* ; Neurofibromin 1/metabolism* ; GTPase-Activating Proteins ; Mutation ; Genetic Predisposition to Disease ; Genetic Therapy

The GATOR1 complex is located at the upstream of the mTOR signal pathway and can regulate the function of mTORC1. Genetic variants of the GATOR1 complex are closely associated with epilepsy, developmental delay, cerebral cortical malformation and tumor. This article has reviewed the research progress in diseases associated with genetic variants of the GATOR1 complex, with the aim to provide a reference for the diagnosis and treatment of such patients.
Humans ; GTPase-Activating Proteins/metabolism* ; Signal Transduction/genetics* ; Mechanistic Target of Rapamycin Complex 1/metabolism* ; Epilepsy/genetics* ; Neoplasms

Studies on coat protein I (COPI) have contributed to a basic understanding of how coat proteins generate vesicles to initiate intracellular transport. The core component of the COPI complex is coatomer, which is a multimeric complex that needs to be recruited from the cytosol to membrane in order to function in membrane bending and cargo sorting. Previous structural studies on the clathrin adaptors have found that membrane recruitment induces a large conformational change in promoting their role in cargo sorting. Here, pursuing negative-stain electron microscopy coupled with single-particle analyses, and also performing CXMS (chemical cross-linking coupled with mass spectrometry) for validation, we have reconstructed the structure of coatomer in its soluble form. When compared to the previously elucidated structure of coatomer in its membrane-bound form we do not observe a large conformational change. Thus, the result uncovers a key difference between how COPI versus clathrin coats are regulated by membrane recruitment.
ADP-Ribosylation Factor 1 ; chemistry ; metabolism ; Animals ; Coatomer Protein ; chemistry ; metabolism ; Cytosol ; chemistry ; metabolism ; GTPase-Activating Proteins ; chemistry ; metabolism ; Humans ; Membranes, Artificial ; Rats

There remains a significant gap in our quantitative understanding of crosstalk between apoptosis and necroptosis pathways. By employing the SWATH-MS technique, we quantified absolute amounts of up to thousands of proteins in dynamic assembling/de-assembling of TNF signaling complexes. Combining SWATH-MS-based network modeling and experimental validation, we found that when RIP1 level is below ~1000 molecules/cell (mpc), the cell solely undergoes TRADD-dependent apoptosis. When RIP1 is above ~1000 mpc, pro-caspase-8 and RIP3 are recruited to necrosome respectively with linear and nonlinear dependence on RIP1 amount, which well explains the co-occurrence of apoptosis and necroptosis and the paradoxical observations that RIP1 is required for necroptosis but its increase down-regulates necroptosis. Higher amount of RIP1 (>~46,000 mpc) suppresses apoptosis, leading to necroptosis alone. The relation between RIP1 level and occurrence of necroptosis or total cell death is biphasic. Our study provides a resource for encoding the complexity of TNF signaling and a quantitative picture how distinct dynamic interplay among proteins function as basis sets in signaling complexes, enabling RIP1 to play diverse roles in governing cell fate decisions.
Animals ; Apoptosis ; Caspase 8/metabolism* ; GTPase-Activating Proteins/metabolism* ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; Necroptosis ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism*

Previous study on the gene expression profile of human MDS by using microarray discovered that transcription of RAP1GAP was up-regulated, which was confirmed by quantitative RT-PCR in expanding cohort of MDS patients. This study was pourposed to investigate the expression of RAP1GAP in human MDS and its clinical relevance. The expression of RAP1GAP in bone marrow cells of 19 MDS patients was detected by flow cytometry and was compared with that in patients with non-malignant blood diseases and acute leukemias, meanwhile the relevance between expression level of RAP1GAP and hemoglobin, leukocytes, platelets, blasts percentage in bone marrow cells and IPSS score was analyzed. The results indicated that the expression level of RAP1GAp in MDS patients significantly increased as compared with patients with non-malignant blood diseases or AML (8.42 +/- 8.37% vs 2.97 +/- 4.75% or 2.26 +/- 4.24%). Among MDS patients, the expression level of RAP1GAP in MDS-RA was significantly higher than that in MDS-RAEB (11.64 +/- 9.07% vs 4.37 +/- 4.65%). However, no definitive correlation of expression level with above-mentioned clinical parameters was found in detected patients with DMS. In conclusion, the expression of RAP1GAP in MDS patients obviously increases, the relationship between expression level of RAP1GAP and laboratory hematological parameter and IPSS score does not be confirmed. The role played by RAP1GAP expression in the pathogenesis of MDS and its clinical significance during progression of MDS towards AML deserves further studies.
Adult ; Aged ; Aged, 80 and over ; Female ; Flow Cytometry ; GTPase-Activating Proteins ; genetics ; metabolism ; Gene Expression Profiling ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; genetics ; metabolism

G3BP (Ras-GTPase-activating protein SH3 domain binding protein), a protein which binds to RasGAP SH3 domain, belongs to RNA-binding protein family, implicating in the downstream of Ras signaling. G3BP harbors the activities of endoribonuclease and DNA helicase, and can induce stress granules formation. G3BP plays a general role in the signal pathways of cell proliferation, differentiation, apoptosis and RNA metabolism. It has been shown to be over-expressed in a number of human malignancies and has a close relationship with tumor invasion and metastasis. Given that it has been implicated in several pathways that are known to be involved in cancer biology, G3BP may provide a new target for cancer therapy.
Animals ; Carrier Proteins ; genetics ; metabolism ; DNA Helicases ; Drug Delivery Systems ; GTPase-Activating Proteins ; therapeutic use ; Humans ; Molecular Sequence Data ; Neoplasms ; drug therapy ; metabolism ; pathology ; Peptide Fragments ; therapeutic use ; Phosphorylation ; Poly-ADP-Ribose Binding Proteins ; RNA Helicases ; RNA Recognition Motif Proteins ; Signal Transduction ; ras GTPase-Activating Proteins ; metabolism ; src Homology Domains ; genetics

Influenza virus assembly requires the completion of viral protein and vRNP transport to the assembly site at the plasma membrane. Therefore, efficient regulation of intracellular transport of the viral proteins and vRNPs to the surface of the host cell is especially important for virus morphogenesis. Influenza A virus uses the machineries of host cells to transport its own components including ribonucleoproteins (vRNPs) and three transmembrane proteins hemagglutinin (HA), neuraminidase (NA) and matrix 2 protein (M2). It has been shown that newly synthesized vRNPs are associated with active form of Rab11 and accumulate at recycling endosomes adjacent to the microtubule organizing center (MTOC) following nuclear export. Subsequently, they are transported along the microtubule network toward the plasma membranes in cargo vesicles. The viral transmembrane proteins are translated on the rough endoplasmic reticulum and transported to the virus assembly site at the plasma membrane. It has been found that several host factors such as ARHGAP21 and GTPase Cdc42 are involved in regulation of intracellular trafficking of influenza A virus transmembrane proteins including NA. In this review, we will highlight the current knowledge about anterograde transport and its regulation of the influenza A virus transmembrane proteins and genome in the host cytoplasm.
Cytoplasm ; metabolism ; GTP Phosphohydrolases ; metabolism ; GTPase-Activating Proteins ; metabolism ; Genome, Viral ; Hemagglutinin Glycoproteins, Influenza Virus ; metabolism ; Humans ; Influenza A virus ; genetics ; pathogenicity ; physiology ; Neuraminidase ; metabolism ; Protein Transport ; Ribonucleoproteins ; metabolism ; Viral Matrix Proteins ; metabolism ; cdc42 GTP-Binding Protein ; metabolism

OBJECTIVETo analyze the expression of deleted in liver cancer 1 (DLC1) and phosphorelated focal adhesion kinase (p-FAK) in breast cancer tissue to further understand the molecular mechanisms of the carcinogenesis and metastasis of breast cancer.

METHODSImmunohistochemistry was employed to determine the protein level of DLC1 and p-FAK in 61 breast cancer, 30 benign breast disease and the adjacent normal breast tissues.

RESULTSThe positivity rates of DLC1 differed significantly between breast cancer, benign and normal tissues (34.43%, 80.00% and 76.67%, respectively, P<0.001). The positivity rates of p-FAK in the 3 tissues were 77.05%, 33.33% and 26.67%, also showing significant differences (P<0.001). The aberrant expression of DLC1 showed an inverse correlation to p-FAK (κ=-0.4591). Both DLC1 and p-FAK were closely correlated to the carcinogenesis, clinical stage, PR and lymphatic metastasis of breast cancer (P<0.05), but not to the patients age, pathological subtype, familial history, ER or CerbB-2 (P>0.05).

CONCLUSIONThe abnormal expression of DLC1 and p-FAK might participate in the carcinogenesis, progression, and metastasis of breast cancer. The role of DLC1 and p-FAK might be related to the regulation of progestone. DLC1 and p-FAK may serve as candidate markers for early diagnosis, prognostic evaluation and target treatment of breast cancer.

Adult ; Breast Neoplasms ; metabolism ; pathology ; Carcinoma, Ductal, Breast ; metabolism ; pathology ; Female ; Focal Adhesion Kinase 1 ; metabolism ; GTPase-Activating Proteins ; metabolism ; Humans ; Lymphatic Metastasis ; Middle Aged ; Phosphorylation ; Prognosis ; Receptors, Progesterone ; metabolism ; Tumor Suppressor Proteins ; metabolism