Alteration of Mitochondrial Proteome Due to Activation of Notch1 Signaling Pathway

Crosstalk between Notch signaling Pathway and Glutamine uptake during Jurkat T cell activation

“…Hey1 is a member of the basic helix-loop-helix-Orange family of transcriptional repressors that mediate Notch signaling [16], and it is one of the well-characterized target gene of Notch activity [14]. Previous studies have shown that Hey1 overexpression can deregulate glutamine metabolism similar to Notch1 overexpression in K562 [11]. Jurkat-Hey1 cells upon activation by PHA/PMA did not show an increase in glutamine consumption (Fig1G).…”

“…All calculations were performed using Microsoft Office Excel. Results & Discussion Notch signaling pathway is downregulated upon Jurkat T cell activation Jurkat T cells are inherently independent on exogenous glutamine for cell survival along with a high expression of Notch1 intracellular domain [14] but upon artificial increase of glutamine consumption, Notch signaling pathway activity was found to decrease [11]. It has also been shown that supplementation of glutamine in exogenous media leads to the maximization of IL2 secretion [15].…”

“…Thus, Jurkat T cell activation is associated with a deregulation of the canonical Notch pathway. A recent study has demonstrated that in K562 cells, increase in Notch1 activity deregulates glutamine consumption and makes the cells independent of glutamine for survival or maintenance of ATP/ADP ratio [11]. Increase in glutamine consumption is an important metabolic adaptation during the process of T cell activation, and it can regulate the cytokine release via a ERK-dependent pathway in isolated murine CD4 + T cells [6].…”

“…The regulation of mature T cell activation and differentiation by Notch signaling is ambiguous and the exact mechanisms are not clear [10]. Recently, it has been shown that glutamine consumption is deregulated by Notch signaling pathway [11]. Upon interaction between Notch receptor and its ligand, there is a cleavage of the Notch transmembrane protein releasing the Notch intracellular domain (NICD) which then translocates to the nucleus and cooperates with the DNA-binding factor RBP-Jκ (CBF1, Suppressor of Hairless, and Lag-1-CSL) and its co-activators to promote transcription [12].…”

Mitochondrial dependency in progression of acute myeloid leukemia

“…Again evolutionarily conserved developmental pathway, Notch signaling pathway, has been implicated in the progression of AML. Recently, it has been shown that Notch signaling pathway suppresses growth and survival of AML cells and using Notch agonist peptide is a novel therapeutic approach which causes apoptosis in AML patient samples (Kannan et al, 2013) and activation of Notch pathway using Notch intracellular domain in K562 cells decreased glutamine consumption (Basak et al, 2014). Thus the interplay of signaling pathways, mitochondrial metabolism and its communication with the rest of the cell is emerging to be important regulators for the development, maintenance and progression of AML.…”