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CD4+ T Regulatory Cells and Modulation of Undesired Immune Responses
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Rosa Bacchetta, Megan K. Levings, Maria-Grazia Roncarolo
Another subset of CD4+ Tr cells was identified in studies of oral tolerance. Th3-cell clones, isolated from mice that were orally tolerised to myelin basic protein, suppress induction of EAE via a TGF-β-dependent mechanism.78 CD4+ Tr cells which protect from EAE also arise in mice or rats, following oral administration of copolymer 1 (Cop-1).79 Interestingly, T-cell lines generated from Cop-1-tolerant animals produce high levels of IL-10 and TGF-β, but little IL-2 or IL-4. Th3, like Tr1 cells and CD4+CD25+ Tr cells, must be activated via the TCR to be suppressive and mediate bystander suppression.80 In patients suffering from multiple sclerosis, oral treatment with myelin basic protein (MBP) and proteolipid protein (PLP) induces a significant increase in the frequency of MBP or PLP-specific T cells that secrete TGF-β.81 These data suggest that cells equivalent to murine TGF-β-producing Th3 cells78 also exist in humans. The specialized environment of the oral mucosa and the selected subsets of resident DC are likely important factors for the differentiation of Th3 cells. Further studies are required to clarify whether the Th3 cells induced during oral tolerance are related to Tr1 or CD4+CD25+ Tr cells. One important difference between Th3 and Tr1 cells appears to be that Th3 cells require IL-4 for their differentiation.80
Organ-specific autoimmune diseases
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, George C. Tsokos
Glatiramer acetate (Copaxone, copolymer-1 [COP-1]), a synthetic basic copolymer of four amino acids designed to resemble MBP epitopes, without the ability to induce T-cell proliferation, has been used with some success. Administration of this product reduces the frequency of relapses of MS, lessens disease activity as measured by MRI, and can induce neurological improvement.
The Anticancer Potential of the Bacterial Protein Azurin and Its Derived Peptide p28
Published in Ananda M. Chakrabarty, Arsénio M. Fialho, Microbial Infections and Cancer Therapy, 2019
Ana Rita Garizo, Nuno Bernardes, Ananda M. Chakrabarty, Arsénio M. Fialho
Upon entering cancer cells, azurin is directed to the nucleus and connects with high affinity through the region of p28 to a hydrophobic region inside of the DNA-binding domain of tumor-suppressor protein p53 (21 kDa; 393 amino acids). This binding forms a complex without altering the conformation of p53, blocking its binding with the E3 ubiquitin ligase Cop1, thereby inhibiting the proteasomal degradation of p53 [16, 25, 26]. p53 is involved in numerous cellular processes, including transcription, DNA repair, genomic stability, and cell cycle control, being able to induce cellular death by apoptosis. In human cancers, this protein can suffer from inactivation by oncogenes [27, 28] and it is known that the E3 ubiquitin ligase Cop1 is overexpressed in breast, ovarian, and hepatocellular carcinomas [29], which contributes to the accelerated degradation of the p53 protein and attenuation of the tumor-suppressor function of p53 [30]. In addition, mutations within the DNA-binding domain of this protein are found in >50% of human cancers and may significantly modify the p53 secondary structure, impairing its function [31].
COP1 facilitates the proliferation, invasion, and migration of glioma cells by ubiquitination of DLG3 protein
Published in Neurological Research, 2023
Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase, which facilitates the degradation of substrates via ubiquitin-mediated protein degradation, thereby modulating diverse cellular functions and participating in pivotal physiological processes related to cancer progression [5]. Interestingly, both oncogenes and tumor suppressor genes, such as JUN, members of the ETS variant family, and p53, are demonstrated to be the ubiquitinated targets of COP1, which means that COP1 itself can act as both a tumor promoter or suppressor [6]. Accumulating studies have revealed the association between COP1 overexpression and accelerated cancer progression, including bladder cancer [7], pancreatic cancer, and breast cancer [8]. COP1 is highly expressed in grade III/grade Ⅳ glioma tissues and glioma cells, and COP1 overexpression expedites glioma cell proliferation by repressing p53 [9]. Nevertheless, the interactive molecules of COP1-mediated ubiquitination in glioma cell proliferation, invasion, and migration have not been fully clarified yet.