Download Apoptosis Oncogenes

Apoptosis
Oncogenes
Srbová Martina
Cell Cycle
Control point
Cyclin B
Cdk1
Cyclin D
Cdk4
Cdk6
Cyclin A
Cdk2
Cyclin E
Cdk2
Cyclin-dependent kinase (Cdk) have to bind a cyclin to become active
Regulation of Cell Cycle
1. Cyclin-dependent kinase (Cdk)
cyclin
Phase
specific
synthesis
Phase-specific
phosphorylation of
proteins required in
the cell cycle
Regulation of Cell Cycle
2. Retinoblastoma protein (pRb)
E2F
Gene transcription:
DNA polymerase,
dihydrofolate
reductase, thymidin
kinase, S phase cyclin
Regulation of Cell Cycle
3. Protein p53, the guardian of the genome
Great DNA damage
high p53 conc.
In over 50% of cancers, the p53 genes are muted or lost.
Regulation of Cell Cycle
4. Growth factor signal transduction
PDGF
PDGF
PDGFR
↑conc. of GF  cell division
GF receptor – tyrosin kinase
domain
PDGF activates Ras
Ras-GTP activates a kinase
cascade
Ras inactivates itself
Mutation in Ras gen – 30% of
human cancer
Y – tyrosin residues
Jun, Fos
APOPTOSIS
Apoptosis
• Programmed cell death
• Elimination of unwanted cells
- embryonic development
- diseased cells,
- tumor cells,
- cells with irreparably damaged DNA
•
shrinking of nucleus, chromatin
condensation
•
formation of small blebs –
apoptotic bodies
•
Without inflammatory response
http://medicinembbs.blogspot.cz/2011/03/programmed-cell-death-apoptosis.html
Membrane blebbing
Fagocytosis
Apoptotic bodies
Apoptosis
Perforin
Granzyme B
Caspase – cystein-containing aspartate proteinases
Death receptor pathway
(extrinsic pathway)
DISC – death inducing signaling complex
Source: http://accessscience.com/content/Death%20receptors/YB100016
Mitochondrial pathway
(intrinsic pathway)
Bak and Bax oligomerize
to form pores
cytochrome c passes
into cytoplasm
Substrate
proteolysis results
in apoptosis
Bcl-2-like proteins:
1) pro-apoptic BAX, BAK, BID
2) anti-apoptic Bcl-2, Bcl-XL
Apaf1 – apoptotic protease activating factor 1
Integration between the death receptor and
mitochondrial pathway
Death receptor pathway
Mitochondrial pathway
Apoptotic signal
Truncated
BID
Cytochrom c
Apaf- 1
Caspase 8
Execution caspases
Caspase 9
Substrates of execution caspases
Caspases
Caspase – cystein-containing aspartate proteinases
Initiator caspases 2,8,9
Execution caspases 3,6,7
Caspases are created from inactive procaspases
Procaspase 8
Caspase 8
Active caspase
Caspases
Target molecules:
Lamins
Poly-ADP-ribosa-polymerase (PARP)
DNA-dependent proteinkinase
Actin
Detection of apoptosis
Exposition of fosfatidyl serine – annexin V
http://www.nature.com/nrm/journal/v2/
n8/fig_tab/nrm0801_627a_F2.html
http://clip.lf2.cuni.cz/file/8.pdf
Detection of apoptosis
DNA fragmention – DNA ladder
http://www.mnc.toho-u.ac.jp/v-lab/macrophage/english/eng02.html
http://www.itsbio.co.kr/main/goods_view.php?category2=60&no=129
ONCOGENES
ONCOGENES
• Proto-oncogenes – genes that encode proteins that promote
cell division or that promote resistence to apoptosis
• Their activating mutation or overexpression results in
increased actvity unregulated cell division or resistence to
apoptosis
• Mutations in proto-oncogens  oncogens
• Only one allele of proto-oncogene needs to be converted to
an oncogene to cause a pro-proliferative or anti-apoptic effect
in a cell
Transforming mutation in proto-oncogenes
Protooncogenes
Activators of cell division
•
•
•
•
•
Growth factors ( PDGF)
Growth factor receptor (PDGFR)
Kinases and kinase cofactors (Cyklins, Cdk, MAPKs)
Transcription factors (Myc, Jun, Fos, E2F)
Signal transduction proteins ( Ras)
Activators of apoptic resistence
• Apoptosis regulators ( Bcl-2, Bcl-XL, Mdm2)
Tumor suppressor genes
• Products of tumor supresssor genes suppress the cell division cycle
or promote apoptosis
• Tumor suppressor gene must lose activity to contribute to cancer
• Both alleles of a tumor suppressor gene must be inactivated or lost
in order to eliminate their tumor suppression activity from a cell
• Retinoblastoma (rb) and p53 genes
• BRCA1, BRCA2
Summary
• Apoptosis can protect organisms from the negative effect of mutation by
destroying cells with irreparably damaged DNA before they proliferate.
• Just as an excess of growth signal can produce an excess of unwanted
cells, the failure of apoptosis to remove excess or damadged cells can
contribute to the cancer.
• Transformation into a malignant cell results from abnormalities in the
normal growth regulatory program caused by gain-of- function mutation
in proto-oncogens.
• However, loss-of-function mutation also must occur in the tumor
suppressor genes for full transformation to a cancer cell
Sources:
• Devlin, T. M. Textbook of biochemistry: with clinical
correlations. 6th edition. Wiley-Liss, 2006.
• Marks´ Basic Medical Biochemistry, A Clinical Approach, third
edition, 2009 (M. Lieberman, A.D. Marks)
• Color Atlas of Biochemistry, second edition, 2005 (J. Koolman
and K.H. Roehm)