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Ca2+ Modulation System of Myometrial Contraction During Gestation
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
It has been found that application of the protein kinase activator (phorbor ester and phosphadidylserine) to skinned smooth muscle fibers that were maximally contracted with Ca2+ induced relaxation concomitant with MLC phosphorylation,34,35 and application of the protein kinase activator markedly decreased its affinity for MLCK to inhibit actin-activated myosin ATPase.30,63 In myometrium, the involvement of Ca2+-independent PKC in the absence of extracellular Ca2+ raises oxytocin-induced contractions of rat uterine smooth muscle.43 Pretreatment of PDB in a Ca2+-free relaxing solution inhibited the subsequent Ca2+-induced contractions of skinned strips (Izumi, unpublished observation). It is reported in skinned chicken gizzard fibers that the constitutive active catalytic subunit of PKC is PKM. PKM attenuated a submaximal contraction that was accompanied by a reduction in the rate of ATP hydrolysis in fibers and phosphorylation of MLC.4,68 Prolonged association of PKC with the sarcolemma can result in proteolysis to release PKM, which could then diffuse through the cytosol and phosphorylate myosin at PKC-specific sites, causing a reduction in actomyosin ATPase and relaxation of the muscle or inhibition of contraction in response to appropriate agonists.4,34-36 Thus, it seems likely that downregulation of PKC diminishes the contractile response in the absence of extracellular Ca2+.
Dysregulated metabolism: A friend-to-foe skewer of macrophages
Published in International Reviews of Immunology, 2023
Keywan Mortezaee, Jamal Majidpoor
PKM2 is an important metabolic regulator that is upregulated in cancer. PKM2 is a potential biomarker for lung cancer diagnosis. Upregulation of PKM2 in such cancer and further interaction with its receptor integrin β1 is contributed to the metastasis [90]. PKM2 dimer is transferred into nucleus. Here, it becomes active, interacts with HIF-1α [51] and enhances bonding between HIF-1α with hypoxia response elements (HREs) of target genes, such as pro-glycolytic enzymes. The PKM2 coactivator function is induced by PHD3, knockdown of which hampers interaction between PKM2 with HIF-1α, attenuates uptake of glucose and lactate generation and boosting consumption of O2 by cancer cells. Based on the Warburg effect, cancer cells show reduced consumption of O2 and increased glycolysis rate [91].
New insights into the metabolism of Th17 cells
Published in Immunological Medicine, 2023
Pyruvate kinase muscle isozyme 2 (PKM2) is an enzyme that is involved in the final step of glycolysis (Figure 1). PKM2 is also a requisite for Th1 and Th17 cell differentiation. The pharmacologic inhibition of PKM2 by Shikonin or its silencing reduces Th1 and Th17 cell differentiation and ameliorates disease activity in EAE [49]. TEPP-46 has been shown to induce PKM2 tetramerization, block PKM2 nuclear translocation and inhibit Th1 and Th17 polarization as well as EAE development [50]. PKM2 translocates into the nucleus and interacts with STAT3, leading to its activation and subsequent increase in Th17 cell differentiation [51]. Interestingly PKM2 binds calcium/calmodulin-dependent protein kinase IV (CaMK4), a serine/threonine kinase [49] (Figure 1). CaMK4 is overexpressed in lupus T cells, and inhibition of CaMK4 by KN-93 ameliorates disease activity in MRL/lpr, lupus-prone mice and EAE mice [52,53]. CaMK4 enhances pyruvate kinase activity and glycolysis [49]. GLUT1 expression is increased in T cells from the patients with SLE compared to healthy controls [54]. The CaMK4 inhibitors reduce the GLUT1 expression of lupus T cells [54]. Thus, CaMK4 enhances glycolysis via the glucose transporter and PKM2.
TKP, a Serine Protease from Trichosanthes kirilowii, Inhibits Cell Proliferation by Blocking Aerobic Glycolysis in Hepatocellular Carcinoma Cells
Published in Nutrition and Cancer, 2022
Aerobic glycolysis, which is a metabolic characteristic of cancer cells, could provide cancer cells with energy and metabolic intermediates for inducing the rapid proliferation of cancer cells (17, 18). Unlike normal cells, tumor cells mainly rely on glycolysis to produce energy even in the presence of sufficient oxygen (19). Pyruvate kinase (PK) is a rate-limiting enzyme in the glycolysis process. There are four isoforms of pyruvate kinase including PKR, PKL, PKM1, and PKM2 (20). Among them, PKM2 highly expressed in cancer cells and plays a decisive role in aerobic glycolysis (21, 22). PKM2 catalyzes the conversion of phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and adenosine triphosphate (ATP) in the final step of the glycolytic pathway (23). Moreover, PKM2 in the nucleus also indirectly mediates aerobic glycolysis by regulating aerobic glycolysis-related proteins, including GLUT1, LDHA, PDK and itself (24–26). PKM2 expression is regulated at the level of transcribed PKM pre-mRNA by splicing factor such as heterogeneous nuclear ribonucleoprotein 1 (HnRNPA1). C-Myc up-regulates the transcription of HnRNP family proteins and thus increases the PKM2 expression in many cancers, which in turn promotes glycolysis and tumor cell proliferation (27).