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Transcript of Oncogene etc
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TUMOR SUPPRESSOR GENES
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Tumor suppressor genes encode proteins that have at least
one of the following functions:
1- Proteins that slow or inhibit progression through a
specific stage of cell cycle e.g. p2land p16.
2- Checkpoint control proteins that arrest cell cycle if DNA
is damaged or chromosomes are abnormal e.g. p53.
3- Receptors that function to inhibit cell proliferation.
4- Proteins that promote apoptosis e.g. protein Bax.
5- DNA repair enzymes (BRCA 1
).
They are termed anti-oncogenes, their mutations remove
certain control on growth and proliferation which play a
major role in the development of cancer.
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Tumor Suppressor Genes That
Directly Regulate the Cell Cycle
The two best understood cell cycle
regulators that are also tumor suppressorsare the retinoblastoma (Rb) andp53 genes.
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The proteins induced by E2F includecyclin E, cyclin A, cdc25A (an activating
protein phosphatase), and proteins requiredto bind at origins of replication to initiateDNA synthesis.
The synthesis of cyclin E allows it tocomplex with Cdk2, forming another activecyclin complex that retains activity into S
phase . Cyclin A activates Cdk2. Thus, eachphase of the cell cycle activates the nextthrough cyclin synthesis. The cyclins areremoved by regulated proteolysis.
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I- Rb (Retinoblastoma) Tumor
Suppressor Gene
The protein product (pRb) is a nuclear phosphoproteinand its phosphorylation oscillates during cell cycle.During the G0 or G1, the protein is present in
dephosphorylated form, its phosphorylation increasesin late G and S phases.
a- The dephosphorylated form of pRb:
1- It inhibits cell proliferation through binding with
certain transcription factors.2- It binds certain viral proteins and produces
inactivation of these proteins.
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I- Rb (Retinoblastoma) Tumor
Suppressor Gene
b- The phosphorylated form of pRb:Phosphorylation of pRb is initiated by CDK-cyclin
complexes in mid G1. Phosphorylation of pRbproduces release and activation of transcription
factors, which stimulate transcription of the geneswhose products are used in replication (enzymesneeded for DNA synthesis).
Phosphorylation of pRb is maintained throughout the
S, G2 and M phases by different CDK-cyclincomplexes. After cell mitosis, the fall of CDK cyclin complexes leads to dephosphorylation ofpRb.
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The main tumors in which inactivation of
pRb is an important cause include tumors of
the retina (retinoblastoma), lung cancers,
adenocarcinoma of prostate and tumors of
bone and connective tissues.
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Disease Example:
RetinoblastomaAn example of a cancer caused by a tumor suppressormutation is retinoblastoma. About one-half ofretinoblastoma cases are familial, with the phenotype
following an autosomal dominant inheritance pattern.Penetrance for heterozygous gene carriers isapproximately 90%. The predisposition toretinoblastoma is caused by the inheritance of amutation of RB1, a tumor suppressor gene onchromosome 13; however, inheritance of this mutationalone is not sufficient to produce a tumor. For this tohappen, the developing fetus must experience a secondmutation in the other copy of RB1 in a specific
retinoblast (i.e., a somatic mutation).
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II-p53 Tumor Suppressor Gene
This is an important example for tumor suppressor genes,
which encodes a protein termed p53 (its molecular weight
equals 53 kDa). It is a nuclear phosphoprotein and acts as a
transcriptional regulator (regulating certain genes thatparticipate in cell cycle).
The level of p53 increases after exposure to agents that
damage DNA. This causes G1 specific cell cycle arrest and
allows time for DNA repair to occur. If the damage cannot be
repaired, p53 can trigger apoptosis, so the damaged cells die.
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It acts as a guardian of the genome or a molecular
policeman by the following mechanisms:
1-Moderate DNA damage activates expression ofp53 that stimulates expression of a cyclin kinaseinhibitor protein (CIP) termed p21. The latter
binds to CDK-cyclin complexes, causing arrestin G1 and G2.
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2-In response to extensive DNA damage,
p53 activates genes that induce
apoptosis, i.e. bax gene.
3-It binds many viral proteins forming
inactive polymeric complex.
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Absence or mutations of p53 is associated with
genome instability and increases the occurrence oftumors. Mutations of p53 gene occur frequently in
may types of cancer. These mutations may be due
to exposure to environmental factors, for example:
- Aflatoxins (a fungal toxin) acts as a potent
hepatocarcinogen.
- Lung cancer in many cases is associated with
smoking or exposure to chemicals e.g.benzo(a)pyrene.
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ONCOGENESOncognes are genes that encode
proteins capable of causing cancer.
Oncogenes were first recognized as
unique Genes of tumor-causing viruses
that are responsible for the process oftransformation (viral oncogene)
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Proto-Oncogenes:
Normal cells containe DNA sequences similar-if not
identical-to those of the viral oncogenes.
The genes present in normal cells thus have been
designated proto-oncogenes, and their products arebelieved to play important roles in normal
differentiation and other cellular process.
The product of the myc oncogene, originally found
in chicken myelocytoma viruses, is a DNA-binding
protein, which may affect the control of mitosis.
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Mechanisms for Conversion of Proto-oncogenes
to Oncogenes Five mechanisms are mainly responsible for this conversion as follows:1- Promoter insertion: Some viruses act through this mechanism e.g. avian
leukemia virus.
2- Enhancer insertion: Many viruses act through this mechanism.
3- Chromosomal translocation: The basis of translocation is that a piece of onechromosome is split off, then joined to another chromosome that brings agrowth- regulatory gene under control of different promoter and causesinappropriate expression of the gene. For example, Philadelphia chromosomethat produces increased activity of the tyrosine kinase and transforms normalcells to leukemic cells.
4- Gene amplification: it is present in many tumor cells. The increased amount ofgene products produced by gene amplification may play a role in theprogression of tumor cells.
5- Point mutation: This produces changes in the protein product of the gene.
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Conversion of a Proto-oncogene to Oncogene
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Conversion of the Abl proto-oncogene into
oncogene in patients with chronic myelogenous
leukemia (CML) by chromosome translocation
(Philadelphia chromosome )
p
q
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Philadelphia chromosome The results from a reciprocal translocation
between the long arms of chromosome 9 and 22.As a consequence, a fusion protein is produced
containing the N terminal region of the Bcr proteinfrom chromosome 22 and the C-terminal region of
the Abl protein from chromosome 9. Ablis aproto-oncogene, and the resulting fusion
protein (Bcr-Abl) has lost its regulatory region andis constitutively active. When active, Ablstimulates the Ras pathway of signal transduction,leading to cell proliferation.
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Burkitts lymphoma, a general name for anumber of types of B cell malignancies, results from a
translocation between chromosomes 8 and 14. Thetranslocation of genetic material moves the proto-
oncogene transcription factorc-myc(normally found
on chromosome 8) to chromosome 14. The
translocated gene is now under the control of thepromoter region for the immunoglobulin heavy chain
gene, which leads to inappropriate and overexpression
ofc-myc.The result may be uncontrolled cell
proliferation and tumor development. All subtypes ofBurkitts lymphoma contain this translocation.
Epstein- Barr virus infection of B cells is also
associated with certain types of Burkitts lymphoma.
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Chromosomal translocation (Burkitts
lymphoma).
Burkitts lymphoma is a fast-growing cancer ofhuman B lymphocytes. In certain cases, a reciprocal
translocation between chromosomes 8 and 14 are
involved.
C-MYC
8
p
q
14
Break
H chain gene
Break
8 8
p
q
14 14
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Schematic representation showing how the translocation involved
in Burkitts lymphoma may activate the C-MYCproto-oncogene.
A: A small segment of chromosome 14 prior to the translocation.
The segment shown contains the genes encoding regions of heavychains of immunoglobulins.
B: Following the translocation, the previously inactive
C-MYCgene is placed under the influence of enhancer sequences
in the genes encoding the heavy chains and is thus activated,
resulting in transcription.
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A combination of activation of proto-
oncogenes combined with inactivation of
tumor suppressor genes is involved Incolorectal and probably most cancers
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Tumor Suppressor GenesOncogenes
Normal version of gene is typicallyinvolved in controlling cell
proliferation (e.g., cell cycle control,
cell adhesion control)
Mutation is typically a loss of
function
Mutations of both copies (two hits)
of the gene are typically necessary
to promote tumor growth
Normal version (proto-oncogene) isusually involved in promoting cell
growth/proliferation
Mutation is typically a gain of
function
A mutation of one copy of the gene
in a cell is sufficient to promote
tumor growth
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DEVELOPMENT OFCANCER
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Cell Proliferation Cell Death
Homeostasis
Regulation of Cell Cycle:
Cell Cycle Check points
Control of Apoptosis
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Cell Proliferation
Cell Death
Neoplasm
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Types of Tumor Cells Epithelial cells: Carcinoma
Connective tissues (fibroblast, muscle):
Sarcoma
Hematopoietic cells: Leukemia
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DEVELOPMENT OF CANCERCancer cells have the following characteristics:
1- Cancer cells can multiply in the absence of growth promotingfactors required for proliferation of normal cells and are resistant
to signals that normally program cell death or apoptosis.2- Cancer cells invade surrounding tissues, often by breaking the
basal laminas and spread through the body to establish secondaryareas of growth (metastases), this is due to secretion of proteasesthat degrade the surrounding extracellular matrix.
Two classes of genes: tumor-suppressor genes and proto-oncogenesplay a key role in cancer induction. These genes encode manyproteins that help the control of cell growth and proliferation.Mutations affecting these genes may result in production ofcancer (converted into oncogenes).
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Several types of gene mutations may participate in cancer
development, which include the following:
1- Misexpressed growth factors: Cancer rarely arises from mutation
of genes encoding growth factors that result in autostimulation ofcell proliferation.
2- Mutation causing autoactivation of growth factor receptors: Some
types of mutations may result in production of receptors that
transmit growth signals in absence of a normal ligand that result in
production of some types of cancer.
3- Overexpression of growth factor receptors: Also, mutations
leading to overexpression of a normal receptor protein can be
oncogenic e.g. breast cancer.
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4- Active signal transduction protein: Many
oncogenes encode proteins that act as
intracellular transducers. These proteins aid intransmitting signals from a receptor to a cellular
target and stimulate growth e.g. Ras protein.
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Ras is a class of G-proteins. Mutated Ras
remain in the active form (Ras-GTP
complex) and acts as a growth-promoting
signal even in the absence of growth
factors. MAP-kinase is a protein kinase
that is activated in response to stimulationby many different growth factors and
mediates cellular response by
phosphorylating specific target proteinse.g. transcription factors.
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5- Inappropriate transcription factors: Most
oncogenes encode proteins that bind to
DNA and modify the rate of geneexpression.
6- Mutations causing loss of cell cycle
control: This may be due to one of the
following examples:
- Overexpression of cyclins.- Loss of genes encoding pRb and cyclin-kinase
inhibitors (p16 & p21), both defects can cause
unregulated cell cycle control.
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7- Mutations affecting genome stability:
Cancer cells are defective in one or more
of the check control points which normallyprevent cells with damaged DNA or
abnormal chromosomes from dividing or
that cause such cells to undergo
programmed cell death e.g. mutation
affecting p53 occurs in more than 50% of
human cancers.
8- Defects in DNA repair systems: as in
cases of xeroderma pigmentosum.
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Viral Infections and
CarcinogenesisSome viruses are carcinogenic (oncogenic
viruses), for example:
1- Some types of adenovirus are known to
cause cell transformation.
2- Epstein-Barr virus is associated with
lymphoma and nasopharyngeal carcinoma.
3- Hepatitis B virus is a major cause of many
primary liver cancer.
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TUMOR MARKERSMany tumors are characterized by the presence of abnormal genes,
enzymes, proteins and hormones, which can be used as markers forthese tumors.
For the detection of abnormal genes, we may use different techniquese.g. in situ hybridization or PCR based techniques (see recombinantDNA technology). Also, the detection of the specific DNA forcertain specific tumors in serum, urine and peritoneal fluid is nowavailable. These techniques help in the early detection of cancer.
The measurement of certain specific markers in serum is useful andnow it is essential for diagnosis and for follow up of cases, forexample:
a- Carcinoembryonic antigen (CEA) in cancer colon, lung, breast and
pancreas.b- Alpha-feto protein (AFP) in liver cancer.
c- Prostatic acid phosphatase in prostate cancer.
d- Prostatic specific antigen (PSA) in prostate cancer.
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Clinical Correlate Translocations
and Cancer
Although most of our discussion deals with inheritedchromosome alterations, rearrangements in somatic cellscan lead to the formation of cancers by altering the geneticcontrol of cellular proliferation.
A classic example is a reciprocal translocation of the longarms of chromosomes 9 and 22, termed the Philadelphiachromosome. This translocation alters the activity of theabl proto-oncogene . When this alteration occurs inhematopoietic cells, it can result in chronic myelogenous
leukemia. More than 100 different chromosome rearrangements
involving nearly every chromosome have been observed inmore than 40 types of cancer.
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One important translocation is the Philadelphia
chromosome, involving chromosomes 9 and 22
and occurring in chronic myelogenous leukemia.
This produces abnormal juxtaposition of the BCR
gene (breakpoint cluster gene) on chromosome 22
with part of the C-ABL gene on chromosome 9.Normally, C-ABL codes a protein-tyrosine kinase.
The juxtaposition resuIts in a chimeric BCR-ABL
mRNA, which encodes t bcr-abl fusion protein
displaying increased tyrosine protein kinaseactivity. This increased activity transforms the
normal cell to a leukemic cell.