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TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
Recent studies have indicated that angiogenesis may be regulated, in part, by TP53 tumor suppressor gene function (Bouvet et al., 1998; Nishimori et al., 1997; Van Meir et al., 1994; Yokota, 2000). Neovascularization may be a direct consequence of TP53 inactivation (Van Meir et al., 1994), possibly due to loss of trans-activation of genes regulated by TP53 (Vogelstein and Kinzler, 1992). It is now thought that the tumor angiogenic switch is triggered as a result of a shift in the balance of stimulators to inhibitors. Negative regulators of angiogenesis, including thrombospondin-1 (TSP1), glioma-derived angiogenesis inhibitory factor (GD-AIF) and brain-specific angiogenesis inhibitor 1 (BAI1) are TP53-target genes. Overexpression of TP53 may inhibit angiogenesis through the upregulation of these genes (Dameron et al., 1994; Furuhata et al., 1996; Nishimori et al., 1997). Loss of wild-type TP53 results in reduced expression of the inhibitor of angiogenesis thrombospondin 1 gene and can switch fibroblasts to the more angiogenic phenotype (Dameron et al., 1994). Early passage Li-Fraumeni cells which carry one wild type TP53 allele secrete large amounts of TSP1. However, the late passage cells undergo an angiogenic switch associated with loss or mutation of the wild type TP53 allele and reduced expression of TSP1 (Dameron et al., 1994; Somasundaram and El-Deiry, 2000). Progression of a glioma to its more malignant form of glioblastoma is usually associated with inactivation of TP53 and striking neovascularization. The expression of BAI1 (containing TSP-type 1 repeats) was absent or significantly reduced in glioblastoma cell lines, suggesting that BAI1 plays a significant role in angiogenesis inhibition, as a mediator of TP53 (Nishimori et al., 1997).
Exendin-4 attenuates inflammation-mediated endothelial cell apoptosis in varicose veins through inhibiting the MAPK-JNK signaling pathway
Published in Journal of Receptors and Signal Transduction, 2020
Apoptotic cells can expose ‘eat me’ signals, which are either newly expressed molecules or existing molecules modified by oxidation, to initiate phagocytosis of the apoptotic cells [81,82]. The process of phagocytosis of apoptotic cells represents an anti-inflammatory mechanism [83–85]. Phosphatidyl serine (PS) localized to the outer leaflet of the plasma membrane is the predominant ‘eat me’ molecule upon apoptosis. Specific molecules such as milk fat globule epidermal growth factor 8 links PS to phagocyte avb3 integrin [86,87], whereas growth-arrest-specific 6 links PS to the receptor tyrosine kinase MER [88]. PS acts as a ligand for the T-cell immunoglobulin domain and mucin domain (TIM)-4 molecule on macrophages and dendritic cells [89–91], and TIM-4 helps promote the uptake of apoptotic cells [92,93]. Two other molecules, brain-specific angiogenesis inhibitor 1 and stabilin-2, have also been shown to mediate uptake of apoptotic cells via recognition of PS [94–96].
Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process
Published in International Reviews of Immunology, 2020
Colonic epithelial cells (CECs) also serve as phagocytic cells, and phagocytose apoptotic cells by recognizing the PS via brain-specific angiogenesis inhibitor 1 (BAI1 or ADGRB1) [62]. Brain-specific angiogenesis inhibitor 1 (BAI1) is a member of the adhesion-family G protein coupled receptors (GPCRs), which via the thrombospondin repeats on its extracellular domain, directly binds to the PS on apoptotic cells to phagocytose them [63]. Thus, BAI1 is an engulfment receptor on CECs that works upstream of Engulfment and Cell Motility (ELMO)/Dedicator of cytokinesis (Dock180)/Rac (a small GTPase) to mediate phagocytosis of apoptotic cells [63]. The phagocytic action of epithelial cells is governed by professional phagocytes, including macrophages, which secrete insulin-like growth factor (IGF)−1 [64,65]. The binding of the released IGF-1 to the IGF-1R expressed on epithelial cells inhibits the phagocytosis of larger apoptotic cells by them. However, it increases the phagocytosis of microvesicles (MVs) by epithelial cells.
Molecular mechanisms that change synapse number
Published in Journal of Neurogenetics, 2018
Alicia Mansilla, Sheila Jordán-Álvarez, Elena Santana, Patricia Jarabo, Sergio Casas-Tintó, Alberto Ferrús
Classical GPCRs such as α2, GABA(B) and CB1 use the βγ dimer to interact with Ca2+ channels, K+ channels or other synaptic proteins that mediate neurotransmitter release. In certain contexts, however, it is the Gα monomer that inhibits presynaptic Ca2+ channels via a cAMP cascade which includes the 4 phosphodiesterase (PDE4). This feature occurs in retinal rod bipolar synapses and is remarkably similar to the Gβγ–cGMP–guanylate cyclase/PDE6 strategy that occurs in phototransduction (Dong, Guo, Ye, & Hare, 2014). This is another example of two similar, albeit distinct, mechanisms to attain the same biological effect, down regulation of Ca2+ influx, operating in two different cellular contexts, synapse transmission and phototransduction, in the retina. A family of GPCRs exhibits an extracellular N-terminal region with multiple adhesion domains connected to the core GPCR moieties by G-protein proteolysis sites. Humans have 33 of them but their functions remain largely unknown. At least one case is involved in spino- and synaptogenesis. The brain-specific angiogenesis inhibitor 1 (BAI1) receptor recruits proteins to synapses through its interaction with the polarity protein Par3/Tiam1 (Duman et al., 2013). Tiam1 is a Rac1-guanine nucleotide exchange factor that becomes restricted to spines, which implies a spatial control of Rac1 activation. This allows Par3 to promote synapse formation (Um et al., 2014).