MBBE 651 - Signal Transduction and Regulation of Gene Transcription

Introduction: Cell behavior is regulated by a complex network of intracellular and extracellular signaling events or “cross talk” between cellular components that are essential for cell survival. Collectively, the various signaling events are characterized as defined consecutive events grouped under the term “Signal Transduction Pathways”. The confluence of genetics, biochemistry and structural biology has given us an increasingly detailed view of how signals are transmitted from cell surface and transcribed into changes in cellular behavior. A major focus in biomedical research over the past two decades has been identification and characterization of the components that make up such signaling pathways. We are now beginning to understand how these signaling pathways are synchronized and, most importantly, impaired in disease states.

Objectives: The main goal of this specialized advanced course is to provide an in-depth comprehensive understanding of the principles of cell signaling pathways and how malfunctions in these pathways can lead to diseased states. This course work is outlined to provide essential elements of cellular mechanisms that allow signaling from the cell surface to the nucleus. Emphasis will be placed on receptors, second messengers, protein kinase cascades, and the regulation of gene transcription.

Specific Aims:

1. Acquire advance knowledge in modern biochemistry and molecular biology.
2. Keep abreast of major developments and acquire a working literature background in any given area.
3. Train graduate students to develop a creative approach to research problems and critically analyze experimental results.

We will achieve specific aim 1, by introducing various aspects of cell signaling outlined in the course below (section A). Specific aims 2 and 3 will be achieved by a seminar presentation and discussion series by the student’s, based on current research articles from their field of study (section B).

A. General Course Outline

• Part 1: Machinery of signal transduction

Will include properties of signals, receptors (including receptor activation), regulators, and the molecules that link receptor and regulator. The process of signaling cascade (s) will be explained by describing central signaling pathways: the Ras-regulated MAPK and PI-3 pathways, the G protein coupled receptor cascades, cyclic nucleotides, calcium signaling, phospholipase, phosphoinositides, products of the sphingolipid pathway (Ceramides), products of the phosphatidylcholine and arachidonic acid metabolism (prostaglandins), protein phosphorylation, kinases and phosphatases (serine/threonine kinases, mitogen-activated protein kinases, histidine phosphorylation, phosphatases).

• Part 2: Effect of signaling cascades on gene transcription (signaling by nuclear receptors)

Will include transcriptional regulation by extracellular signals such as sterol regulatory element-binding proteins (SREBP), regulation of cytoplasmic transcription factor (e.g NF-kB), as well as regulation of transcription by cytokines and growth factors in the control of cell growth and the mechanisms and sites of control including Jun/Fos, Wnt, b-catenin, PPAR, C/EBP, STATs and MEF.

Mechanisms of gene regulation by nuclear receptors, including both the steroid hormone receptors and non-steroid nuclear receptors e.g. the retinoic acid receptors (RAR), PGC-1 and RXR.

• Part 3: Cellular regulation of cell growth, proliferation and cell death

Will include regulation of the cell cycle and the role of the cyclin-dependent kinases, telomerase, Ran, and cell cycle checkpoints. Signaling pathways in apoptosis will include the TNF-receptor family death receptors, caspases, and the intracellular apoptosis signals as well as the role of apoptosis in the lifecycle of cells.

• Part 4: Loss of regulatory control and its consequences

Will involve molecular basis of cancer and metabolic disorders such as diabetes and insulin resistance.

• Part 5: Specialized topics
• Signal transduction to and from adhesion molecules (e.g. ICAM, VCAM)
• Cross talk between mitochondria and nucleus
• Mitochondrial signaling and fatty acids (b-oxidation of fatty acids, role of ADP/ATP antiporter in the uncoupling effect of fatty acids, adenine nucleotide translocation during fatty acid metabolism, uncoupling proteins)
• Nitric Oxide signaling
• Reactive Oxygen Species (ROS) signaling
• Cell signaling and molecular chaperones (heat shock proteins)
• Antisense RNA

B. Discussion series

Will involve student’s choice of research articles based on their filed of study and presentation in class for discussion