Regulation of NRF2 by stably associated phosphoinositides and small heat shock proteins in response to stress.

Reactive oxygen species are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1).

The nuclear phosphoinositide-p53 signalosome in the regulation of cell motility.

Dysregulation of p53 and phosphoinositide (PIPn) signaling are both key drivers of oncogenesis and metastasis. Our recent findings reveal a previously unrecognized interaction between these pathways, converging in the nucleus to form a PIPn-p53 signalosome that modulates nuclear AKT activation and downstream signaling, thereby influencing cancer cell survival and motility. This review examines recent insights into nuclear PIPn signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIPns interact with p53 to form signalosomes that affect cell motility.

Phosphoinositide signaling at the cytoskeleton in the regulation of cell dynamics.

The cytoskeleton, composed of microfilaments, intermediate filaments, and microtubules, provides the structural basis for cellular functions such as motility and adhesion. Equally crucial, phosphoinositide (PIP) signaling is a critical regulator of these processes and other biological activities, though its precise impact on cytoskeletal dynamics has yet to be systematically investigated. This review explores the complex interplay between PIP signaling and the cytoskeleton, detailing how PIP modulates the dynamics of actin, intermediate filaments, and microtubules to shape cellular behavior.

Phosphoinositide signalling in cell motility and adhesion.

Cell motility and adhesion are fundamental components for diverse physiological functions, including embryonic development, immune responses and tissue repair. Dysregulation of these processes can lead to a range of diseases, including cancer. Cell motility and adhesion are complex and often require regulation by an intricate network of signalling pathways, with phosphatidylinositol phosphates (PIPs) having a central role.

Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.

The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes.

Linking Phosphoinositides to Proteins: A Novel Signaling PIPeline.

Phosphoinositide (PIP) signaling plays pivotal roles in myriad biological processes and is altered in many diseases including cancer. Canonical PIP signaling involves membrane-associated PIP lipid second messengers that modulate protein recruitment and activity at membrane focal points. In the nucleus, PIP signaling operates separately from membranous compartments defining the paradigm of non-canonical PIP signaling.

Aryl Hydrocarbon Receptor Knockout Accelerates PanIN Formation and Fibro-Inflammation in a Mutant Kras -Driven Pancreatic Cancer Model.

Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear.

Environmental pollutants and phosphoinositide signaling in autoimmunity.

Environmental pollution stands as one of the most critical challenges affecting human health, with an estimated mortality rate linked to pollution-induced non-communicable diseases projected to range from 20% to 25%. These pollutants not only disrupt immune responses but can also trigger immunotoxicity. Phosphoinositide signaling, a pivotal regulator of immune responses, plays a central role in the development of autoimmune diseases and exhibits high sensitivity to environmental stressors.

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.

Unlabelled: Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1).

Lipid Transfer Proteins and PI4KIIα Initiate Nuclear p53-Phosphoinositide Signaling.

Unlabelled: Phosphoinositide (PIP ) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP complexes (p53-PIP signalosome) that activate Akt by a PI3,4,5P -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP s that is poorly characterized.

Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutant -driven pancreatic cancer model.

Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear.

Chronic jetlag-induced alterations in pancreatic diurnal gene expression.

Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shift work, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking.