BLOK ONCOLOGY

Biochemistry Department Medical Faculty USU

TUMOR GENETICS
PROTOONCOGENES
ONCOGENES TUMORSUPPRESSOR

GENES

CARCINOGENESIS: MOLECULAR MECHANISM OF TUMOR CELLULAR TRANSFORMATION

TUMOR MECHANISM
HOW

TO DETECT A TUMOR HOW TO DIAGNOSED HOW TO UNDERSTAND THE MECHANISM HOW ARE THE MOLECULAR PATHWAY IN WHAT CONDITION COULD WE TREAT THE TUMOR WHAT KIND OF TREATMENT

THE NEW TUMOR DRUGS

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

SRC RAS

FMS Orga nella

Nucleus FOS MYC JUN

FMS

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 C, PI3-K Adaptor proteins : Grb2 SH2 and SH3 domain. Three major pathways : PI3-kinase (PI3-K/AKT pathway, RAS/mitogenactivated 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.

 G-Protein

and Signal transduction

ANY QUESTIONS??

CARCINOGENESIS
MOLECULAR

MECHANISM OF TUMOR CELLULAR TRANSFORMATION

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.

Gene
TRANSCRIPTION

Primary transcript NUCLEUS

Degradation

MODIFICATION / PROCESSING

mRNA

Degradation Transport

mRNA CYTOPLASM

Active degradation

inactive

TRANSLATION

Protein

Degradation

Mechanisms of retroviral oncogenesis.

1. 2. 3.

Slowly transforming viruses. Acutely transforming viruses. Trans-acting retroviruses.

HTLV1

Insertional mutagenesis
Oncogene transduction Affect expression or function of cellular growth and differentiation genes.
( the only human retrovirus known to directly cause cancer).

FREE RADICALS AND INFLAMMATION

ROS OH O2-
(Hydroxyl (Superoxide) radical)

NO

RNS ONOO-

(Nitric Oxide) (Peroxynitrite)

N2O3

Protein Damage
(DNA Repair Enzymes, Caspases)

Lipid Peroxidation MDA

(malondialdehyde)

DNA Damage and Mutation

Nitrosamines/Deamination 8--oxo-dG 8-nitroguanine Etheno Adducts M1G Adduct S-nitrosothiol SSBs DSBs

4HNE
(4-hydroxynonenal)

Arachidonic Acid Cascade Eicosanoids Cell Proliferation

1760-CH

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.