Bio413 Cell Signaling Cell Signaling 2008 Syllabus by malj


									                        Cell Signaling 2008
Instructor: Yinsheng Wan, Ph. D. Associate Professor, Dept of Biology, Providence
College, E-mail:

Textbook: No such books are available, but materials to be covered will be provided
prior to each class.

Relevant Web Sites: and

Brief Course Description:

        The physiological systems in human beings are tightly regulated and if
unchallenged maintain homeostatic. Deviation from homeostasis however causes human
diseases including various types of cancer. For the past two decades, modern
cell/molecular biology techniques have been applied to unravel those regulatory
mechanisms. The complicated process from stimulation such as hormones or
environmental insults to gene expression is now termed cell signal transduction, namely
information flow from cell surface receptor activation to kinase cascade activation to
transcription factor activation to gene expression. This course, which will explore the
convoluted cellular activities upon stimulation, is designed to provide coverage across a
broad spectrum of disciplines including genetics, developmental biology, neurobiology,
immunology, physiology, and cell biology. Molecular targets for drug development will
be also discussed. Class discussion and presentation will focus on reading and
comprehension from most recent scientific literatures and experimental design/methods.
Prerequisites: BIO 200, CHM 201-202. CHM 309 is also highly recommended.

Note: due to the progress made daily in cell signaling field, the lectures will be modified


        At the end of the semester, students are required 1) to remember the terminology
associated with cell signaling, 2) to remember major cell signaling pathways, 3) to read
and comprehend research papers in cell signaling filed and to be able to draw possible
cell signaling pathways, 4) to write research proposal in certain areas, and 5) to work
with others to execute experimentations in cell signaling research.

Course Grade Distribution: Class discussion, 10%, two exams, 80%, one Project
presentation, 10%.
        Class discussion is important for understanding the materials/concepts provided.
Your involvement is mandatory. Since no book is available, please take notes. Two
written exams will be based on the papers, my lectures, our discussion and your notes. To

ensure that you understand the basic concepts and principles of cell signal transduction,
before final exam, a project presentation after reading/digestion of at least 5 review
articles on particular topic is imposed for this course. Your classmates will have a chance
to give you a grade of presentation (1-10). The topics of the presentation and the rules
will be given in the mid-semester.

The topics to be covered in the course include but not limited to the following:

I. The importance of the matrix in signal transduction
Cell surface receptors as reception of extra-cellular signals
Response to extra-cellular stimuli based upon the theory of Yin/Yang balance
Amplification of signal during transmission---a quantitative study
Tyrosine kinase and tyrosine phosphatase
Cell membrane components and adapter proteins required for signal transmission
Upstream and downstream
Signal transduction without cell surface receptor activation
G-protein coupled signaling
The secondary messengers in signal transduction pathways
CAMP, Ca2+, ROS,

II. Various signal transduction pathways from cell surface to nucleus
MAP kinase pathway
SAP/JNK pathway
p38 pathway
ERK pathway
NFkB pathway
Cell survival pathway
Wnt signaling pathway
Jak/Stat pathway
Smad pathway

III. Cross-talks in signal transduction
Cross talk among cell surface receptors, Crosstalks among cytoplasmic components
Translocation of signal components during signal transmission
From cytoplasm to cell membrane
From cytoplasm to nucleus

IV. The end point of signal transduction--- gene transcription
Nuclear receptors and transcription factors
From simple pathway to complex pathway
From single gene expression to multiple gene expression: Superarray as a tool for the
study of multiple gene transcription
Practical application of the signal transduction research

                               Tentative Lecture Schedule

Chapters     Date                 Lecture                                  Remarks

Chapter 1    Jan 18               Introduction to Cell Signaling

Chapter 2    Jan 25               Apoptosis Signaling Transduction
Chapter 3    Feb 1, No class      Reactive Oxygen Species and Hypoxia      AAD, Feb 1-5
                                  Signaling, reading
Chapter 4    Feb 8                NF-B Signaling Pathway and
Chapter 5    Feb 15               PI3K/AKT Cell Survival Pathway

Chapter 6    Feb 22               MAP Kinase Signaling Pathways
             March 7                                                       Mid-term exam

Chapter 7    March 14             RNA Interference And Cell Signaling

Chapter 8    March 28             Senescence and Its Signaling Pathways

Chapter 9    April 4              Caveolins and Cell Signaling, reading    April 5-9, EB 2008
Chapter 10   April 11             Chromatin Remodeling And Gene
Chapter 11   April 18             NO Signaling And Neuronal Diseases

             April 25                                                      Project Presentation

             May 14                                                        Final Exam
Chapter 14                        Cell Cycle And Its Signaling

Chapter 15                        TGF  Signaling
Chapter 16                        EGFR And Its Signaling
Chapter 17                        Cytoskeleton And Cell Signaling
Chapter 18                        Carbohydrate Recognition Signaling

Chapter 19                        MMPs And Cell Signaling
Chapter 20                        G- Protein Signaling or Ca++ Signaling

                    Chapter 1 Introduction to Cell Signaling

Cell Signaling emerges as an important discipline in the interface between current
biology and medicine. Breakthroughs are being made annually if not daily. This chapter
will cover the emergence of Cell Signaling and its unparalleled importance in
understanding the complicated biological system and fighting various diseases including

            Chapter 2. Apoptosis Signaling Transduction Pathway

Apoptosis, or programmed cell death, remains an important event in maintaining cellular
homeostasis. Understanding the mechanisms of apoptosis would help cure or prevent
from various neuronal diseases and cancer. Apoptosis remains a versatile pathway for
therapeutic development. Apoptosis, or programmed cell death, has been a key area of
focus at many pharmaceutical companies. Although the body has several apoptotic
pathways designed to eliminate malignant cells, the mutations that occur in cancer cells
frequently render them ineffective. Thus, therapies that may induce apoptosis in cancer
cells have potential for treating a variety of cancer cells. Scientists have made important
contributions to the understanding of multiple apoptotic pathways.

         Chapter 3. Reactive Oxygen Species and Hypoxia Signaling

Optimum concentration of ROS possesses cell signal functions such as activation of
kinase activities and yet unregulated elevation of ROS could result in deleterious effects
on cellular activities associated with damages of proteins, nucleic acids and lipids. Low
oxygen tension, or hypoxia, occurring in solid tumors, is critical for induction of a
transcription factor, or HIF that facilitates transcription of genes such as VEGF, an
important factor for angiogenesis. HIF is thus considered as a valid target for cancer

            Chapter 4. NF-B Signaling Pathway and Inflammation

NF-B transcription factors play an important role in the regulation of immune response,
embryo and cell lineage development, cell apoptosis, inflammation, cell-cycle
progression, oncogenesis, viral replication, and various autoimmune diseases. The
activation of NF-B is thought to be part of a stress response as it is activated by a variety
of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological
agents, and other stresses. In its inactive form NF-B is sequestered in the cytoplasm,
bound by members of the IB family of inhibitor proteins. The various stimuli that
activate NF-B cause phosphorylation of IB, which is followed by its ubiquitination and
subsequent degradation.

                  Chapter 5. PI3K/AKT Cell Survival Pathway
Since its discovery as a proto-oncogene nearly ten years ago, the serine/threonine kinase
AKT, also known as protein kinase B (PKB), has become a major focus of attention
because of its critical regulatory role in diverse cellular processes, including cancer
progression. The AKT cascade is activated by receptor tyrosine kinases, integrins, B- and
T-cell receptors, cytokine receptors, G-protein coupled receptors, and other stimuli that
induce the accumulation of phosphatidylinositol 3,4,5 triphosphates, (PtdIns(3,4,5)P3),
by the phosphoinositide 3-kinase (PI3K). The three AKT isoforms (Akt1, Akt2 and Akt3)
thus mediate many of the downstream events regulated by PI3K. For instance, AKT is a
major regulator of insulin signaling and glucose metabolism. Akt controls cell growth
through its effects on the mTOR and p70 S6 kinase pathways, as well as the cell cycle
and cell proliferation through its direct action on the CDK inhibitors, p21 and p27, and
indirectly by affecting the levels of cyclin D1 and p53. AKT is also major mediator of
cell survival by directly inhibiting different pro-apoptotic signals such as Bad and the
Forkhead family of transcription factors, or indirectly by modulating two central
regulators of cell death such as p53 and NF-B. AKT signaling in endothelial cells plays
also critical roles in the regulation of vascular homeostasis and angiogenesis. These
findings have turned AKT/PKB into important therapeutic target for the treatment of
cancer, diabetes and stroke.

                  Chapter 6. MAP Kinase Signaling Pathways
Mitogen-Activated Protein Kinases include, ERK, JNK and p38 protein kinases,
activated by growth factors, cytokines and environmental stress. MAP kinase pathways
are involved in gene expression, cell growth and differentiation, cytoskeleton activity.

Overall Cell regulation

                Chapter 7. RNA Interference And Cell Signaling
Small RNAs make big splash, becoming “BREAKTHROUGH OF THE YEAR of 2002”.
Short stretches of RNA ranging in length from 21 to 28 nucleotides are called small
RNAs. Their role had gone unnoticed until recently, in part because researchers, focused
on the familiar larger RNA molecules, tossed out the crucial small ones. RNA has long
been viewed primarily as an essential but rather dull molecule that ferries the genetic
code from the nucleus to the ribosomes, and helps assemble amino acids during protein
synthesis. Signs that RNA might be more versatile came in the early 1990s, when
biologists determined that some small RNAs could quash the expression of various genes
in plant and, later, animal cells. But they didn't appreciate the molecules' true powers
until 1998. Andrew Fire of the Carnegie Institution of Washington in Baltimore,
Maryland, Craig Mello of the University of Massachusetts Medical School in Worcester,
and their colleagues injected stretches of double-stranded RNA into worms. Double-
stranded RNA forms when a familiar single strand kinks back in a hairpin bend, putting
two complementary sequences alongside each other. To the researchers' surprise, double-
stranded RNA dramatically inhibited genes that had helped generate the RNA in the first
place. This inhibition, which was later seen in flies and other organisms, came to be
known as RNA interference (RNAi). It helped prove that RNA molecules were behind
some gene silencing. Another crucial step came in 2001, when Gregory Hannon of Cold
Spring Harbor Laboratory identified an enzyme, appropriately dubbed Dicer, that
generates the small RNA molecules by chopping double-stranded RNA into little pieces.
These bits belong to one of two small RNA classes produced by different types of genes:
microRNAs (miRNAs) and small interfering RNAs (siRNAs). SiRNAs are considered to
be the main players in RNAi, although miRNAs, which inhibit translation of RNA into
protein, were recently implicated in this machinery as well. To bring about RNAi, small
RNAs degrade the messenger RNA that transports a DNA sequence to the ribosome.
Exactly how this degradation occurs isn't known, but scientists believe that Dicer delivers
small RNAs to an enzyme complex called RISC, which uses the sequence in the small
RNAs to identify and degrade messenger RNAs with a complementary sequence. Such
degradation ratchets down the expression of the gene into a protein. Although quashing
expression might not sound particularly useful, biologists now believe that in plants,
RNAi acts like a genome "immune system," protecting against harmful DNA or viruses
that could disrupt the genome. Developing RNAi-based therapeutics is under way for
several disease areas including: ocular diseases, infectious diseases, oncology, metabolic
disorders, inflammatory disease, central nervous system disease.

               Chapter 8. Senescence and Its Signaling Pathways

The study of human senescence has been fraught with controversy, conflicting theories,
and puzzling data. Indeed, "pure" senescence is often difficult to distinguish from
diseases of old age. Medical science has cataloged many signs of senescence. It manifests
as dozens of changes in cells, tissues, and organs during aging. Human life is supported
by a complex network of biochemical substances and reactions which affect the physical
state and vitality of the body and mind. Senescent changes can be seen in the rate and
outcome of many of these reactions. However, many of these changes are secondary
effects of senescence, rather than primary causes. Senescence is becoming an attended
issue in cancer research similar to apoptosis.

                     Chapter 9. Caveolins and Cell Signaling
Caveolae were initially described some 50 years ago. The identification of a molecular
marker for these domains, caveolin, combined with the possibility to isolate such
cholesterol- and sphingolipid-rich regions as detergent-insoluble membrane complexes
paved the way to more rigorous characterization of composition, regulation, and function.
Experiments with knock-out mice for the caveolin genes clearly demonstrate the
importance of caveolin-1 and -3 in formation of caveolae. Nonetheless, detergent-
insoluble domains are also found in cells lacking caveolin expression and are referred to
here as lipid rafts. Caveolae and lipid rafts were shown to represent membrane
compartments enriched in a large number of signaling molecules whose structural
integrity is essential for many signaling processes. Caveolin-1 is an essential structural
component of cell surface caveolae, important for regulating trafficking and mobility of
these vesicles. In addition, caveolin-1 is found at many other intracellular locations.
Variations in subcellular localization are paralleled by a plethora of ascribed functions for
this protein.

           Chapter 10. Chromatin Remodeling And Gene Regulation
DNA is wound around nucleosomes, which consist of Histones H2A, H2B, H3 and H4.
These proteins all contain positively charged lysine-rich regions that form strong
noncovalent bonds with the phospho-sugar backbone of the DNA double helix. In the
nucleosome-bound state, it is difficult for RNA polymerase to transcribe messages.
Therefore, one of the factors recruited to the proximal promoter by specific transcription
factors is Histone Acetyltransferase (HAT), which acetylates and neutralizes those lysine
residues on the histone core. This DNA/histone binding is much more conducive to
transcription. However, other factors such as the dead box family of SWI ATPases help
push nucleosomes out of the way to further ease transcription. Histone-modifying
enzymes and chromatin remodeling complexes work in concert to condense and
recondense stretches of chromatin. Modification by acetylation to the histone tail is
necessary to decondense the chromatin in the promoter regions but histone acetylation
and modification alone cannot disrupt the structure of the core particle of the nucleosome.
Additional factors are needed to “remodel” the nucleosome cores to permit removal or
repositioning. Chromatin remodeling is recognized to be an important event in gene
regulation that may hold keys for cancer treatment.

               Chapter 11. NO Signaling And Neuronal Diseases

Researchers believed that amino acid arginine was responsible for smooth muscle
relaxation that is endothelial cell dependent. In 1987, nitric oxide (NO) was discovered to
be molecule responsible for that effect. More functions of NO have been uncovered for
the past decade and NO signaling pathways have been unraveled.

       Chapter 12. Cell Adhesion And Its Importance In Cell Signaling
                            And Cell Migration

The role of cell adhesion molecules such as cadherin and integrins in tumor progression
and metastases has been recently implicated in the past ten years. Because of these cell
adhesion proteins role in signaling from the outside to the inside of a cell, the way in
which tumor cells survive and interact with their environment is closely tied to the
expression and/or over-expression of these adhesion molecules. Integrins interact with
the actin cytoskeleton and protein kinases such as FAK, ILK, Src and PKC. This leads to
expression of MAPK and Erk pathways. This can cause up-regulation of MMPs.
Integrins also can be positive mediators of angiogenesis. Cadherin, especially E-
Cadherin, down-regulation has been shown to have metastatic effects. Also, a switch of
E and P-Cadherins to N-Cadherins has been implicated in increased tumor progression.

         Chapter 13. Phosphatases And Regulation of Cell Signaling

Protein phosphatases play important parts in cell signaling, both activating and
inactivating certain pathways. There is great diversity among phosphatases, making them
important in all aspects of signaling and physiology. Phosphatases are potential targets
for cancer therapy by either inhibiting them or activating them to attenuate cell cycle
progression. Research is underway to determine whether targeting phosphatases will be
an effective treatment for cancer.

                     Chapter 14. Cell Cycle And Its Signaling

Regulation of the cell cycle is important because errors can lead to cancer. During most
of the cell cycle, the cell does not require any extra-cellular signals. However, during the
G1 phase, the cell does require these signals up to the restriction point (R) to tell the cell
if it should proceed through R and continue with the rest of the cell cycle. R is near the
end of the G1 phase, just prior to entry into S phase, when DNA is replicated. This serves
as one of the main control points of the cell cycle.

                           Chapter 15. TGF  Signaling

TGF signaling is involved in various cellular processes in a variety of cell types. The
convoluted signaling pathways have been discovered recently and inhibitors are being
developed to target the signaling pathways and eventually to alter the cellular responses
in both normal and cancer cells.

                       Chapter 16. EGFR And Its Signaling

Epidermal Growth Factor (EGF) is a protein that stimulates the growth and division of
epidermal cells and many other cell types. EGF-receptor (EGFR) is a transmembrane
glycoprotein found primarily on cells of epithelial origin. EGFR is involved in maturation
of epithelial tissues during embryogenesis. In adults, EGFR plays a role in organ repair
and wound healing and cell proliferation. More and more data indicate an unavoidable
role of EGFR in cancer development and metastasis. EGFR is considered as a very
important target for cancer treatment.

                  Chapter 17. Cytoskeleton And Cell Signaling

Cytoskeleton has long been considered important in cell division. Not until recently has
its cell signaling functions have been uncovered. Targeting cytoskeleton is becoming a
valid approach for cancer treatment.

                Chapter 18. Carbohydrate Recognition Signaling

Carbohydrates have been discovered to play important roles in cellular activities such as
Inflammation, immunology-immune cell transmigration and response. Carbohydrates are
also involved in cell adhesion, tumorigenesis, metastasis, cell growth, differentiation and

                     Chapter 19. MMPs And Cell Signaling

MMPs serve to degrade the extracellular matrix which is important for many cellular
responses. Abnormal development and pathological conditions are the result of MMPs
not being regulated. MMP inhibitors have the ability to inhibit angiogenesis which is a
promising avenue in cancer research.


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