activation of oncogenes, causes of oncogenesis and mechanism of oncogenesis.

1. Factors Controlling
Growth, Oncogenesis.
BY: TUBA TAHIR

2. Oncogenesis:
 Oncogenesis is also called tumorigenesis or
carcinogenesis.
 Oncogenesis means Tumor or mass formation, Is
the formation of cancer whereby normal cells are
transformed into cancer cells. The process is
characterized by changes at cellular, genetic and
epigenetic levels and abnormal cell division.

3.  Cell Cycle Check Points:
 There are many check points in a cell cycle which
regulates the growth processes in a cell.
 It prevents entry into the next phase of cell cycle.
 It is also called DNA damage check points.

5. Oncogene:
 An oncogene is a gene that has the potential to
cause cancer or tumor. All are involved in cancer and
uncontrolled cellular growth.
 About 100 different oncogenes have been identified.
 Can be various kinds of proteins. such as Growth
factors regulatory genes involved in control of cell
multiplication.

7. Proto-oncogenes:
 Normal form of gene found in the cell that is
involved in positive regulation of the cell cycle.
 Functions of proto- oncogenes:
1- Help to regulate cell growth and differentiation
2- Involved in signal transduction
3- Involved in execution of mitogenic signals.

8. Proto-oncogene Activation:
 There are three main types of proto-oncogene
activation that can occur:
1- Increased enzyme or protein activity
2- Regulation loss
3- Increased protein concentration
 Increased protein concentration results from
various genetic mechanisms that include:
eg; Insertions, deletions, or point mutations.

10. Activation of oncogene:
 Mutations that occur among proto-oncogenes,
which can be termed as normal genes, lead to the
activation of oncogenes.
 In a general sense, proto-oncogenes aid in the
differentiation and growth regulation in cells by
coding for proteins as well as in signal transduction.
Once activated, a proto-oncogene becomes an
oncogene.
 Upon oncogene activation, the cell multiplies and
grows out of control and cause cancer.

11. Activation of
oncogene.
Mutation occurs and cause
cancer.

13.  Causes of oncogenesis:
 Genome instability.
 DNA variability or damage.
 Genetic factors.
 Contribution of field defects.
 Epigenetic reasons.

14. 1-Genome instability:
 It refers ta a high frequency mutation within the
genome of cellular lineage.
 These mutations can include changes in nucleic
acid sequences, within the genome of
chromosomal rearrangements or aneuploidy.
 Genome instability may result from failures at
different steps of the DNA cycle, from replication to
segregation.

16. 2-DNA Damage:
 DNA damage is a change in the basic structure
of DNA that is not itself replicated when the DNA is
replicated.
 A DNA damage can be a chemical addition or
disruption to a base of DNA or a break in one or
both chains of the DNA strands.

18. 3-Genetic and epigenetic
factors:
 It includes changes in nucleotide sequence of
genomic sequence.
 Epigenetics involves genetic control
by factors other than an individual's DNA
sequence.
 Epigenetic changes can switch genes on or off and
determine which proteins are transcribed.
 Epigenetics is involved in many normal cellular
processes.

19. 4-Contribution of Field Defects:
 A field defect is a field of pre-malignant tissue in
which a new cancer is likely to arise.
 Recent research indicates that cells within a field
defect characteristically have an increased
frequency of epigenetic alterations and these may
be fundamentally important as underlying factors
in progression to cancer.

20. Causes of DNA Damage:
 DNA damage occurs continuously as a result of
various factors such as,
 Intracellular metabolism.
 Replication.
 Exposure to genotoxic agents, such as ionizing
radiation.
 Environmental agents such as UV light.

21.  Result of DNA Damage:
 DNA damage could result in changes or mutations
within the cell genomic material.
 Replication forks can be stalled due to damaged
DNA.
 Double strand breaks are also a form of DNA
damage.
 All these changes results in the uncontrolled cell
division and cause tumor or cancer.

23.  Factors controlling Growth,
oncogenesis:
 There are five kinds of factors that are classified on
the basis of the functional and biochemical
properties of protein products of their normal
counterparts (proto-oncogenes). These are
 Growth factors
 Growth factor receptors
 Signal transducers
 Transcription factors
 Programmed cell death regulators.

24. 1-Growth Factors:
 A growth factor is a naturally occurring substance
capable of stimulating cell proliferation and cellular
differentiation. Target cells must possess a specific
receptor in order to respond to a specific type of
growth factor.
 Usually it is secreted as,
Protein, or a
Steroid hormone.
 Growth factors are important for regulating a
variety of cellular processes.

26. 2- Growth factor Receptor:
 Growth factor receptors are molecular machines
that transmit information in a unidirectional fashion
across the cell membrane
 Growth factor receptors are collectively as they
have characteristic protein structure consisting of
three principal domains:
(1) the extracellular ligand-binding domain.
(2) the transmembrane domain.
(3) the intracellular tyrosine kinase catalytic
domain.

27. 3- Signal Transducers:
 Mitogenic signals are transmitted from growth
factor receptors on the cell surface to the cell
nucleus through a series of complex interlocking
pathways collectively referred to as the signal
transduction cascade.
 Signal transducers are often converted to
oncogenes by mutations that lead to their
unregulated activity, which in turn leads to
uncontrolled cellular proliferation.

28. 4-Transcription Factor:
 Transcription factors are nuclear proteins that
regulate the expression of target genes or gene
families.
 Transcriptional regulation is mediated by protein
binding to specific DNA sequences or DNA
structural motifs, usually located upstream of the
target gene.
 Transcription factors often belong to multigene
families that share common DNA-binding domains
such as zinc fingers.

29. 5-Programmed Cell Death Regulation:
 Normal tissues exhibit a regulated balance between
cell proliferation and cell death. Programmed cell
death is an important component in the processes
of normal embryogenesis and organ development.
A distinctive type of programmed cell death, called
apoptosis.
 This process is characterized morphologically by
condensation of the cell nucleus, and cleavage of
genomic DNA.

30.  Mechanism of Oncogene Activation:
 The activation of oncogenes involves genetic
changes to cellular protooncogenes.
 The consequence of these genetic alterations is to
confer a growth advantage to the cell. Three
genetic mechanisms activate oncogenes in human
1-Mutation.
2-Gene amplification.
3-Chromosome rearrangements.

31. 1-Mutations:
 Mutations activate protooncogenes through
structural alterations in their encoded proteins.
These alterations, which usually involve critical
protein regulatory regions, often lead to the
uncontrolled, continuous activity of the mutated
protein.
 Various types of mutations, such as base
substitutions, deletions, and insertions, are capable
of activating protooncogenes.

32. Types of mutation:

33. 2-Gene Amplification:
 Gene amplification refers to the expansion in copy
number of a gene within the genome of a cell. Or
 An increase in the number of copies of a gene.
There may also be an increase in the RNA and
protein made from that gene.
 Gene amplification is common in cancer cells, and
some amplified genes may cause cancer cells to
grow or become resistant to anticancer drugs.

34. 3-Chromosomal Rearrangements:
 Chromosomal rearrangements are often detected
in hematologic malignancies as well as in some
solid tumors. These rearrangements consist mainly
of chromosomal translocations and, less frequently,
chromosomal inversions.
 Chromosomal rearrangements can lead to tumors
via two different mechanisms:
(1)the transcriptional activation of
protooncogenes.
(2)the creation of fusion genes.

36. Oncogenic Viruses:
 Oncogenic viruses can be divided into two groups
on the basis of their genetic material.
 DNA tumor viruses
 RNA tumor viruses.

37. Capabilities of Oncogenes:
 Oncogenes imitate the growth signaling patterns of
normal cells by developing the capability to create
their own growth factors, which in turn allows for
autocrine stimulation.
 Oncogenes also can create changes in the structure
or expression or cell surface receptors. These
changes inhibit and alter the signals sent to the cell
regarding the encouragement of
growth/proliferation.

38.  Tumor Suppressor Gene:
 A tumor suppressor gene, or anti-oncogene, is
a gene that regulates a cell during cell division and
replication.
 If the cell grows uncontrollably, it will result
in cancer.
 In combination with other genetic mutations, tumor
suppressor gene could allow the cell to grow
abnormally.

39. Summary:
 Two classes of genes, oncogenes and tumor
suppressor genes, link cell cycle control to tumor
formation and development. Oncogenes in their
proto-oncogene state drive the cell cycle forward,
allowing cells to proceed from one cell cycle stage
the next.
 This highly regulated process becomes
due to activating genetic alterations that lead to
cellular transformation. Tumor suppressor genes,
the other hand, restrict cell cycle progression. Their
control over cell division is lost with genetic
alterations leading to their inactivation and as a
result it causes cancer or tumor.