K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)

8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)

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BLOK ONCOLOGY

Biochemistry DepartmentMedical Faculty USU


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TUMOR GENETICS

PROTOONCOGENESONCOGENESTUMORSUPPRESSOR GENES

CARCINOGENESIS:MOLECULAR MECHANISM OF TUMORCELLULAR TRANSFORMATION
http://localhost/var/www/apps/conversion/tmp/Breast%20Cancer%20Cell.wmvhttp://localhost/var/www/apps/conversion/tmp/Breast%20Cancer%20Cell.wmv


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TUMOR MECHANISM

HOW TO DETECT A TUMORHOW TO DIAGNOSEDHOW TO UNDERSTAND THEMECHANISMHOW ARE THE MOLECULARPATHWAYIN WHAT CONDITION COULD WETREAT THE TUMORWHAT KIND OF TREATMENT


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THE NEW TUMOR DRUGS


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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 contactinhibition, anchorage independentgrowth, ability to form tumors whentransplanted into nude mice.


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Proto-oncogene. Potential to become activated into a

cancer causing oncogene. Have been found in all multicellular

organisms. Would be involved : basic essentialfunctions of the cell related to control ofcell proliferation and differentiation.

In normal cell : expression is tightlycontrolled.


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Cell Cycle


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Cell-cycle control system is based oncyclically activated protein kinases :-Cdks (cyclin dependent kinases)-Cyclins (cdk regulator protein),without cyclins cdk is inactive.


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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 G 1 provided byPDGF,EGF,followed by progression factors:IGF to progress through the cell cycle.

Action via autocrine and paracrinemodel.


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2.Growth factor receptors

Link the information from extracellularenvironment (GF) to a number ofdifferent intracellular signalingpathways.

The most important : transmembranereceptor tyrosine kinases.


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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/mitogen-activated protein kinase (MAPK)pathway, JAK/STAT pathway.


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4. Nuclear proto-oncogene andtranscription 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.


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G-Protein and Signal transduction
http://localhost/var/www/apps/conversion/tmp/G%20Protein.movhttp://localhost/var/www/apps/conversion/tmp/Siklik%20c-AMP.movhttp://localhost/var/www/apps/conversion/tmp/Siklik%20c-AMP.movhttp://localhost/var/www/apps/conversion/tmp/G%20Protein.movhttp://localhost/var/www/apps/conversion/tmp/G%20Protein.movhttp://localhost/var/www/apps/conversion/tmp/G%20Protein.mov


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ANY QUESTIONS??


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CARCINOGENESIS

MOLECULAR MECHANISM OF TUMORCELLULAR TRANSFORMATION


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Mechanisms of oncogene activation

1. Structural alteration. Point mutations Chromosomal translocation Truncated form of protein (transition

mutation)

2. Amplification3. Deregulated expression Insertional mutagenesis Translocation.


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http://content.nejm.org/content/vol358/issue25/images/large/08f1.jpeg


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Tumor suppressor genes

Play an important role intumorigenesis.Involved in the control of abnormalcell proliferation.Loss or inactivation : association withthe development of malignancy.


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Viral Oncogene

Three major mechanisms by whichan infectious agent can cause cancer

1. Persistent infection chronicinflammation repeated cycles ofcell damage and cellular proliferation

accumulate genetic mutations initiation and promotion of cancer .


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2.Direct participation of infectiousagents in the transformation of thecell through activation of cellularoncogene pathway.

3. Relevant to HIV : infection mayresult in immunosuppression and

decreased recognition of infected ortransformed cell by host immunesystem.


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Gene

Primarytranscript

mRNA

mRNA

Protein

TRANSCRIPTION

Degradation

MODIFICATION / PROCESSING

Degradation

Degradation

Active inactivedegradation

Transport

TRANSLATION

NUCLEUS

CYTOPLASM


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Mechanisms of retroviraloncogenesis.

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 todirectly cause cancer).


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1760-CH

FREE RADICALS AND INFLAMMATION

ROSOH O2 - (Hydroxyl (Superoxide)radical)

RNSNO ONOO - N2O3 (Nitric Oxide) (Peroxynitrite)

MDA(malondialdehyde)

4HNE(4-hydroxynonenal)

DNA Damageand Mutation

Nitrosamines/Deamination8--oxo-dG8-nitroguanineEtheno AdductsM1G AdductS-nitrosothiolSSBs DSBs

LipidPeroxidation

Arachidonic AcidCascade

Eicosanoids

CellProliferation

Protein Damage (DNA Repair Enzymes, Caspases)


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Apoptosis

Programmed cell deathIntracellular machinery responsiblefor apoptosis is called caspases.Caspases

Synthesized in the cell as inactiveprecursor called procaspasesUsually activated by cleavage ataspartic acids by other caspases.
http://localhost/var/www/apps/conversion/tmp/Apoptosis.wmvhttp://localhost/var/www/apps/conversion/tmp/Apoptosis.wmv


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K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)