Ras proteins and the proteins that regulate Ras activity have been highly

conserved in evolution,
and genetic analyses in Drosophila and C. elegans provided the first clues
as to how receptor
tyrosine kinases activate Ras. Genetic studies of photoreceptor cell
development in the
Drosophila eye have been particularly informative.

An SH Adaptor Protein Couples Receptor

Tyrosine Kinases
to Ras: Evidence from the Developing
Drosophila Eye 35
The Drosophila compound eye consists of about 800 identical units called
ommatidia,each
composed of 8 photoreceptor cells (R1-R8) and 12 accessory cells ( Figure
15-51). The eye
develops from a simple epithelial sheet, and the cells that make up each
ommatidium are
recruited from the sheet in a fixed sequence by a series of cell-cell
interactions. Beginning with
the development of R8, each differentiating cell induces its uncommitted
immediate neighbor to
adopt a specific fate and assemble into the developing ommatidium
( Figure 15-52).
The development of the R7 photoreceptor, which is required for the
detection of ultraviolet light,
has been studied most intensively, beginning in 1976 with the description of
a mutant fly called
sevenless (sev), in which the only observed defect is that R7 fails to
develop. Such mutants are
easy to select on the basis of their blindness to ultraviolet light. The sev
gene was eventually
isolated and shown to encode a receptor tyrosine kinase that is expressed
on R7 precursor cells.
Further genetic analysis of mutants in which R7 development is blocked but
the Sev protein itself
is not affected led to the identification of the gene bride-of-sevenless
(boss), which encodes the
ligand for the Sev receptor protein. Boss is a seven-pass transmembrane
protein that is
expressed exclusively on the surface of the adjacent R8 cell, and when it
binds to and activates
Sev, it induces the R7 precursor cell to differentiate into an R7
photoreceptor. The Sev protein is

also expressed on several other precursor cells in the developing

ommatidium. But none of these
cells contact R8; therefore, the Sev protein is not activated, and the cells do
not differentiate into
R7 photoreceptors. Although one suspects that multicellular organisms
make widespread use of
cell-surface-bound signaling ligands like Boss, such molecules have been
hard to identify and
characterize by standard biochemical techniques. The identification of Boss
illustrates the power
of the genetic approach.
The components of the intracellular signaling pathway activated by Sev in
the R7 precursor cell
proved more difficult to identify than the receptor or its ligand because they
are used by cells in a
variety of developing organs besides the eye and mutations that inactivate
them are lethal. Some
of these mutations, however, are lethal only when both copies of the gene
are affected and so
can be maintained in heterozygous animals, carrying one normal and one
mutant copy of the
gene. By isolating such mutants, as well as by using other genetic
strategies, several genes
encoding some of the intracellular signaling proteins were identified. One
encodes a Ras protein.
Whereas flies in which both copies of the ras gene are inactivated by
mutation die, flies with only
one inactivated copy survive but lack R7. Conversely, if one of the ras
genes is rendered
overactive by mutation, R7 develops even in mutants in which both sev and
boss are inactive.
Thus activation of Ras seems to be necessary and sufficient to induce R7
differentiation. A
second gene, son-of-sevenless (sos), encodes a guanine nucleotide
releasing protein (GNRP),
which is required for the Sev receptor tyrosine kinase to activate Ras. A
third gene encodes a
Sem-5-like protein called Drk ( downstream of receptor kinases), which
couples the Sev receptor
to the Sos protein; the SH2 domain of Drk binds to activated Sev, while the
two SH3 domains are
thought to bind to Sos. A fourth gene encodes a GTPase-activating protein
(GAP). If this gene is

inactivated, R7 develops even if sev has been inactivated, presumably

because Ras is
hyperactive in the absence of inhibition by GAP ( Figure 15-53). In this
signaling system,
therefore, and in most others that have been studied, the activation of Ras
by receptor tyrosine
kinases depends on the activation of a GNRP rather than on the
inactivation of a GAP.
Once activated, Ras relays the signal downstream by activating a
serine/threonine
phosphorylation cascade that is highly conserved in eucaryotic cells from
yeasts to humans. A
crucial component in this cascade is a novel type of protein kinase called
MAP-kinase, which we
consider next.
Corticosteroid hormones such as cortisone, for
example, which inhibit the activity of the phospholipase in the first step of
the eicosanoid
synthesis pathway shown, are widely used clinically to treat noninfectious
inflammatory diseases,
such as some forms of arthritis. Nonsteroid anti-inflammatory drugs such
as aspirin and
ibuprofen, by contrast, block the first oxidation step, which is catalyzed by
cyclooxygenase.
Certain prostaglandins that are produced in large amounts in the uterus at
the time of childbirth
Aspirin causes several different effects in the body, mainly the reduction of
inflammation, analgesia (relief of pain), the prevention of clotting, and the
reduction of fever. Much of this is believed to be due to decreased production of
prostaglandins and TXA2. Aspirin's ability to suppress the production of
prostaglandins and thromboxanes is due to its irreversible inactivation of the
cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and
thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl
group is covalently attached to a serine residue in the active site of the COX
enzyme. [1] This makes aspirin different from other NSAIDs (such as diclofenac
and ibuprofen), which are reversible inhibitors. However, other effects of aspirin,
such as uncoupling oxidative phosphorylation in mitochondria, and the
modulation of signaling through NF-B, are also being investigated.
Protooncogenes are genes that code for proteins responsible for proliferation.
Mutations in protooncogenes can lead to an increase in protein expression,
hyperactivity (i.e. gain-of-function ) and/or loss of regulation. This mutated form
is called oncogene.
Receptor

o a region of tissue, or a molecule in a cell membrane, which

responds specifically to a particular neurotransmitter, hormone,
antigen, or other substance.
Ligand

o
o

a molecule that binds to another (usually larger) molecule

Role of p53 and apoptosis in carcinogenesis.

Wang XW1.

Author information

Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health,

Bethesda, Maryland 20892, USA. xin-wei-wang@nih.gov
1

Abstract
Carcinogenesis is a process that converts normal cells from controllable to uncontrollable growth.
Coordinate regulation of the rates of cell proliferation and cell death is an important determinant in
maintenance of homeostasis. Loss of control of this balance is central to the development of cancer.
This loss may be due to genetic alteration in either growth promoting genes resulting in constitutive
activation or negative growth regulating genes such as tumor suppressor genes. Recent advances in
studying the molecular mechanisms related to the etiology of cancer have provided further
understanding of these pathways. Earlier studies have been primarily concerned with cell proliferation
resulting from activation of oncogenes. However, many recent studies have focused on the induction
of cell death. The recognition of the importance of apoptosis, a distinct mode of cell death, in
maintenance of genomic stability was further prompted by studying the mechanism of the tumor
suppressor gene product p53, as well as many other oncogenes and tumor suppressor genes. For
example, many oncogenes appear to act as potent inducers of apoptosis through activation of p53
dependent apoptosis pathways. Therefore, one possible mechanism for tumor suppression involves
activation of apoptosis pathways in cells at risk of neoplastic transformation. These studies have
provided extensive knowledge of the signal transduction pathways in response to genotoxic stress
and promoted mechanistic research related to the apoptosis pathways. These studies also provide a
perfect explanation that p53 is a key element in maintaining genomic stability and loss of the p53
function is a common event during carcinogenesis. This chapter will mainly focus on the role of
apoptosis in carcinogenesis. In particular, I will summarize recent studies related to the mechanisms
of p53 and its role in this process.

p 5 3 is the most commonly mutated gene in human cancers and more than 50% of
human cancers contain p 5 3 mutations. In the past decade, the roles of p53 in human
cancers have been investigated extensively in many aspects and intervention to restore
wild-type p53 activities is an attractive approach for cancer therapy. Hepatocellular
carcinoma (HCC) is one of the most common cancers worldwide and most current
therapies are of limited efficacy. This review updates the focused points of correlations
between p53 and HCC in the regards such as carcinogenesis, progression, diagnosis,
and treatment. The p53 protein and anti-p53 antibodies are related to the clinical
characteristics and diagnosis of HCC. Also stated are p53 protein as a marker of
malignancy compared with -fetoprotein and ferritin, p53 products for the treatment of
HCC, approaches for p53 to get into the target, p53 as a factor to predict the prognosis
of HCC, as well as prospects of p53 for the treatment of HCC in the future. However,
knowledge about the roles of p53 in HCC is still incomplete and needs to be expanded
by more studies. In the future, the information about p53 and its related items may

become a part of our patient management and serve to achieve the existing therapeutic
strategies of HCC.

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid

chains covalently bonded to a glycerol molecule through ester linkages. One
example, shown on the right, is 1-palmitoyl-2-oleoyl-glycerol, which contains sidechains derived from palmitic acid and oleic acid. Diacylglycerols can also have many
other combinations of fatty acids attached at either the C-1 and C-2 positions or the
C-1 and C-3 positions. 1,2 disubstituted glycerols are always chiral, 1,3 disubstituted
glycerols are chiral if the substituents are different from each other. plasma
membrane, due to its hydrophobic properties. IP3 stimulates the release of calcium
ions from the smooth endoplasmic reticulum, whereas DAG is a physiological
activator of protein kinase C (PKC). The production of DAG in the membrane
facilitates translocation of PKC from the cytosol to the plasma membrane.
Phytochrome It is sensitive to light in the red and far-red region of the visible spectrum. Many
flowering plants use it to regulate the time of flowering based on the length of day and night
(photoperiodism) and to set circadian rhythms
Cryptochromes are a class of flavoproteins that are sensitive to blue light. They are found
in plants and animals. The Role of Cryptochrome 2 in Flowering in Arabidopsis

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