8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
1/40
BLOK ONCOLOGY
Biochemistry DepartmentMedical Faculty USU
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
2/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
3/40
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.wmv8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
4/40
TUMOR MECHANISM
HOW TO DETECT A TUMORHOW TO DIAGNOSEDHOW TO UNDERSTAND THEMECHANISMHOW ARE THE MOLECULARPATHWAYIN WHAT CONDITION COULD WETREAT THE TUMORWHAT KIND OF TREATMENT
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
5/40
THE NEW TUMOR DRUGS
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
6/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
7/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
8/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
9/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
10/40
Cell Cycle
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
11/40
Cell-cycle control system is based oncyclically activated protein kinases :-Cdks (cyclin dependent kinases)-Cyclins (cdk regulator protein),without cyclins cdk is inactive.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
12/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
13/40
2.Growth factor receptors
Link the information from extracellularenvironment (GF) to a number ofdifferent intracellular signalingpathways.
The most important : transmembranereceptor tyrosine kinases.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
14/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
15/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
16/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
17/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
18/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
19/40
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.mov8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
20/40
ANY QUESTIONS??
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
21/40
CARCINOGENESIS
MOLECULAR MECHANISM OF TUMORCELLULAR TRANSFORMATION
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
22/40
Mechanisms of oncogene activation
1. Structural alteration. Point mutations Chromosomal translocation Truncated form of protein (transition
mutation)
2. Amplification3. Deregulated expression Insertional mutagenesis Translocation.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
23/40
http://content.nejm.org/content/vol358/issue25/images/large/08f1.jpeg8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
24/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
25/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
26/40
Tumor suppressor genes
Play an important role intumorigenesis.Involved in the control of abnormalcell proliferation.Loss or inactivation : association withthe development of malignancy.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
27/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
28/40
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 .
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
29/40
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.
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
30/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
31/40
Gene
Primarytranscript
mRNA
mRNA
Protein
TRANSCRIPTION
Degradation
MODIFICATION / PROCESSING
Degradation
Degradation
Active inactivedegradation
Transport
TRANSLATION
NUCLEUS
CYTOPLASM
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
32/40
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).
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
33/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
34/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
35/40
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)
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
36/40
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.wmv8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
37/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
38/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
39/40
8/12/2019 K - 3 & K - 4 Oncogenes & Carcinogenesis (Biokimia)
40/40
Top Related