LIFE305 Cell Signalling in Health and Disease

Lecture on cell signaling during G1/S phase of the cell cycle. Learning outcomes: describe the phases, checkpoints and timing of the cell cycle; explain the regulation of cyclin-dependent kinases (CDKs) by cyclins and CDK inhibitors and describe the role of specific CDKs during the cell cycle; demonstrate depth of understanding of the signalling mechanisms by which retinoblastoma (Rb) protein governs the decision to divide at the G1 restriction point; understand how oncogenic growth factor signa...

Lecture on calcium signaling and calcium-induced toxicity (acute pancreatitis). 12 pages covering the pathogenesis of acute pancreatitis (cellular and organ responses, basolateral instead of apical exocytosis of zymogens, calcium signals in acute pancreatitis - the calcium hypothesis), the importance of mitochondria in determining cell fate (how mitochondria take up calcium leading to a sustained large rise and mitochondrial injury i.e. the mitochondrial permeability transition/MPT), a model for...

Lecture on cyclic AMP (cAMP) signalling to make clear how cAMP performs its role as second messenger and how cAMP-mediated signals are transduced, and to highlight the diversity of cAMP-mediated physiological effects. Covers the production of cAMP (via adenylyl/adenylate cyclase, AC), the structure of AC, the targets of cAMP, how cAMP-dependent protein kinase A (PKA) is activated, how target specificity of PKA is achieved (A-kinase anchoring proteins/AKAPs including Yotiao protein), regulation o...

Detailed notes on calcium signalling and calcium stores, esp. in pancreatic acinar cells (exocrine pancreas). Covers some info on the pancreas, pancreatic juice and acinar cell morphology (apical/basal area, secretory granules, enzyme precursors aka zymogens), physiological calcium distribution (high calcium concentration outside the cell, lower inside the cell and mainly bound to proteins), elementary events of calcium signalling (amplitude modulation i.e. local transients, local oscillations a...

Detailed information on signalling involved in nutrient sensing and the stimulation or inhibition of subsequent metabolic processes. Covers the regulation of glucose uptake in muscle and adipose (fat) tissue by insulin and the molecules involved (PI3K, AKT, glucose transporter GLUT4 in the classical pathway, and also a novel pathway involving Cbl), and how and which molecular mechanisms are activated under energy deprivation (AMPK and mTOR as nutrient sensors). Signalling pathways involved in nu...

In-depth lecture notes on the ubiquitin cycle including the principal enzymes (E1, E2, E3), different types of ubiquitin chains and their functions (signalling, proteosomal degradation, trafficking), and crosstalk between ubiquitination and phosphorylation in the NFkB pathway. The NFkB pathway is also discussed in detail (proteins/posttranslational modifications involved, activation of the pathway, negative feedback loop which inhibits the pathway, and a relatively new model of the pathway invol...

Lecture on the features of IP3 and DAG as second messengers and their role in the activation of PKC. Covers an overview of the PIP2-IP3/DAG-PKC pathway (calcium signalling), details on the IP3 receptor that is responsible for calcium release from the ER (structure, isoforms), specifics of PKC activation (calcium-insensitive vs calcium-sensitive isoforms), techniques to measure PKC activation (FRET with C kinase activity reporter, CKAR) and the role of PKC in acute pancreatitis.

Lecture focussing on reactive oxygen species (ROS) production by NAD(P)H oxidase, xanthine oxidase and mitochondria, the role of antioxidants and antioxidative pathways (bacteria: OxyR, mammals: Keap1/Nrf2), pathways of ROS clearance (superoxide dismutase, catalase, glutathione), the effects of ROS (mitochondrial permeability transition/MPT, lipid peroxidation, changes in the ratio of oxidized vs reduced gluthatione, protein carbonylation), techniques to measure ROS and antioxidant activity (N-a...

Lecture notes covering the Ras-Raf-MEK-ERK (MAPK) pathway including information on signal transduction through the pathway, oncogenic mutations in Ras, the role of posttranslational modifications in regulating protein localization and function in the MAPK pathway, Ras activation by GEFs and inactivation by GAPs, Ras isoforms i.e. H/K/N-Ras and the role of their hypervariable regions (different Ras isoforms have different functions) how Raf is recruited to Ras and activated, and strategies for ta...

General overview of cell signalling: different modes of signalling (juxtracrine, endocrine, autocrine, paracrine), general signalling pathway (stimulus - receptor - transducer - amplifier etc.), 6 different classes of signalling receptors (GPCRs, receptor tyrosine kinases/RTKs...), 11 different classes of intracellular signalling molecules (protein kinases, lipid kinases, phosphatases, adaptors...) and further reading on feedback loops and adaptive signalling.