Genome of Hepatitis B Virus

BLOK ONCOLOGY

Dr. Yahwardiah Siregar, PhD

Dr. Sry Suryani Widjaja, Mkes
Biochemistry Department
 Proto Oncogen and Oncogen
• Oncogen
– Genes that possess the ability to cause cellular
transformation.
– Act in a dominant fashion, either overexpression
or activating mutations.

Cellular transformation.
morphologic changes, loss of contact inhibition,
anchorage independent growth, ability to form
tumors when transplanted into nude mice.
• Proto-oncogene.
– Potential to become activated into a cancer
causing oncogene.
– Have been found in all multicellular organisms.
– Would be involved : basic essential functions of
the cell related to control of cell proliferation and
differentiation.
– In normal cell : expression is tightly controlled.
 Protooncogen products

SIS
ABL

FMS Nucleus
SRC
Orga FOS
FMS
RAS nella MYC
JUN

MOS

ERB-B1
Cell Cycle
• Cell-cycle control system is based on cyclically
activated protein kinases :
• -Cdks ( cyclin dependent kinases )
• -Cyclins ( cdk regulator protein ),without
cyclins cdk is inactive.
 Proto-oncogenes
• 1.Growth Factors
– Stimulate cells in stationary stage to enter the cell
cycle.
– Occurs in a two stage process :
• Stimulation to proceed into G1 provided by
PDGF,EGF,followed by progression factors :IGF to
progress through the cell cycle.
– Action via autocrine and paracrine model.
• 2.Growth factor receptors
– Link the information from extracellular
environment (GF) to a number of different
intracellular signaling pathways.
– The most important : transmembrane receptor
tyrosine kinases.
• 3. Signal transducers.
– Cytoplasmic nonreceptor tyrosine kinases.
– Proteins with enzyme activity such as
phospholipase Cγ, PI3-K
– Adaptor proteins : Grb2
– SH2 and SH3 domain.
– Three major pathways : PI3-kinase (PI3-K/AKT
pathway, RAS/mitogen-activated protein kinase
(MAPK) pathway, JAK/STAT pathway.
• 4. Nuclear proto-oncogene and transcription
factors.
– Involved in the control of gene expression by their
action on DNA itself
– Final site of action for messages sent from GF.
– Level at which control of growth and proliferation.
 Apoptosis
• Programmed cell death
• Intracellular machinery responsible for
apoptosis is called caspases.
• Caspases
• Synthesized in the cell as inactive precursor
called procaspases
• Usually activated by cleavage at aspartic acids
by other caspases.
 Mechanisms of oncogene activation
• 1. Structural alteration.
– Point mutations
– Chromosomal translocation
– Truncated form of protein (transition mutation)
• 2. Amplification
• 3. Deregulated expression
– Insertional mutagenesis
– Translocation.
 Tumor suppressor genes
• Play an important role in tumorigenesis.
• Involved in the control of abnormal cell
proliferation.
• Loss or inactivation : association with the
development of malignancy.
 Viral Oncogene
• Three major mechanisms by which an
infectious agent can cause cancer :
• 1. Persistent infection chronic
inflammation repeated cycles of cell
damage and cellular proliferation
accumulate genetic mutations initiation
and promotion of cancer .
• 2.Direct participation of infectious agents in
the transformation of the cell through
activation of cellular oncogene pathway.
• 3. Relevant to HIV : infection may result in
immunosuppression and decreased
recognition of infected or transformed cell by
host immune system.
Retroviruses
 Gene
TRANSCRIPTION

Primary
Degradation
transcript

NUCLEUS MODIFICATION / PROCESSING

mRNA Degradation

Transport

mRNA Active inactive

degradation

CYTOPLASM TRANSLATION

Protein Degradation
 Mechanisms of retroviral
oncogenesis.
• 1. Slowly transforming viruses.
– Insertional mutagenesis
• 2. Acutely transforming viruses.
– Oncogene transduction
• 3. Trans-acting retroviruses.
– Affect expression or function of cellular growth
and differentiation genes.
• HTLV1 ( the only human retrovirus known to directly
cause cancer).
 Normal Epithelium
APC Mutations (>95%)

Hyperploriferative epithelium

Early adenoma
K-RAS Mutations (30-40%)
Intermediate adenoma

Late adenoma
p53 Mutations ≈ 50%
Carcinoma insitu

Other changes
Metastasis
• http://www.intechopen.com/books/
oncogene-and-cancer-from-bench-to-clinic