* Calcineurin inactivation inhibits pyruvate dehydrogenase complex activity and induces the Warburg effect.
- Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase that connects the Ca2+-dependent signalling to multiple cellular responses. Calcineurin inhibitors (CNIs) have been widely used to suppress immune response in allograft patients. However, CNIs significantly increase cancer incidence in transplant recipients compared with the general population. Accumulating evidence suggests that CNIs may promote the malignant transformation of cancer cells in addition to its role in immunosuppression, but the underlying mechanisms remain poorly understood. Here, we show that calcineurin interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme that connects two key metabolic pathways of cells, glycolysis and the tricarboxylic acid cycle. Mitochondrial-localized calcineurin dephosphorylates PDHA1 at Ser232, Ser293 and Ser300, and thus enhances PDC enzymatic activity, remodels cellular glycolysis and oxidative phosphorylation, and suppresses cancer cell proliferation. Hypoxia attenuates mitochondrial translocation of calcineurin to promote PDC inactivation. Moreover, CNIs promote metabolic remodelling and the Warburg effect by blocking calcineurin-mediated PDC activation in cancer cells. Our findings indicate that calcineurin is a critical regulator of mitochondrial metabolism and suggest that CNIs may promote tumorigenesis through inhibition of the calcineurin-PDC pathway.
=>大きくなる, を増す, 増大させる, 強まる, 増加, 増える, 増やす
Overview of noun increase
The noun increase has 5 senses (first 5 from tagged texts)
1. (49) addition, increase, gain -- (a quantity that is added; "there was an addition to property
taxes this year"; "they recorded the cattle's gain in weight over a period of weeks")
2. (21) increase -- (a change resulting in an increase; "the increase is scheduled for next month")
3. (7) increase, increment, growth -- (a process of becoming larger or longer or more numerous or
more important; "the increase in unemployment"; "the growth of population")
4. (3) increase, increment -- (the amount by which something increases; "they proposed an increase
of 15 percent in the fare")
5. (3) increase, step-up -- (the act of increasing something; "he gave me an increase in salary")
Overview of verb increase
The verb increase has 2 senses (first 2 from tagged texts)
1. (86) increase -- (become bigger or greater in amount; "The amount of work increased")
2. (61) increase -- (make bigger or more; "The boss finally increased her salary"; "The university
increased the number of students it admitted")
--- WordNet end ---