Role of check points in cell cycle regulation as potential target for cancer

1. Presented by
G.Naresh
PC2016206
Check points in cell cycle
regulation
08/08/17 1
Guided by
Dr. Venu Talla
NIPER, Hyderabad

2. Contents
•Introduction
•Phases of cell cycle
•Cell cycle regulators
•Check points in cell cycle regulation
•Summary
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3. Introduction
Cell cycle checkpoints are surveillance mechanisms that
monitor the order, integrity, and fidelity of the major events of
the cell cycle.
These include growth to the appropriate cell size, the
replication and integrity of the chromosomes, and their accurate
segregation at mitosis.
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Kevin J. Barnum and Matthew J. O’Connell, Methods Mol Biol. 2014

4. Reasons to activation of cell cycle
checkpoints
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5. Cell cycle
 The cell cycle is the series of events in which cellular
components are doubled, and then accurately
segregated into daughter cells.
Phases of cell cycle
Interphase
G1
S
G2
Mitotic phase
Mitosis
Cytokinesis
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6. Cell cycle
Mitosis
cytokinesis
Mitotic
phase
interphase
Nutrition
Growth factors
Cell growth
Cell size
Cell growth
DNA relication
DNA Synthesis
Two
daughter
cells
formation
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7. Contd….
 Cell division, cell differentiation and cell death are the
three principal physiological processes that regulate
tissue homoeostasis in multicellular organisms
 The importance of dysregulated cell cycle progression
and cell death in the pathogenesis of major diseases,
such as cancer, ischemia/reperfusion injury,
atherosclerosis, infection, inflammation and neurological
disorders, is now well established
K. G. Wiman & B. Zhivotovsky, J Intern Med 2017
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8. Cell cycle regulators
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These checkpoint signals stop the cell cycle transitions either by inhibiting
the activator or activating the inhibitor
Brian Gabrielli *, et al Defective cell cycle checkpoints as targets for anti-cancer therapies , 2012

9. Cell cycle activators
 The central machines that drive cell cycle progression
are the cyclin-dependent kinases (CDKs).
 These are serine/threonine protein kinases that
phosphorylate key substrates to promote DNA synthesis
and mitotic progression
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Milagros J. Tenga et al; Proteomic snapshot of breast cancer cell cycle:G1/S transition point; 2012

10. Contd….
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Helfrid Hochegger et al molecular cell biology; 2008

11. Mechanism
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Genome
insult to
cell
Yes No
Activates p53 and
arrest the cell cycle
Deactivates and
continuous cell
cycle
Brian Gabrielli *, et al Defective cell cycle checkpoints as targets for anti-cancer therapies , 2012

12. Contd….
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Cell cycle progression is further regulated by two classes of cell cycle
inhibitors
The INK4 proteins
including p16
(INK4a) and p15
(INK4b)
The Cip/Kip family
including p21, p27
and p57.
Specific cyclin–CDK complexes and cell
cycle at specific points
K. G. Wiman & B. Zhivotovsky, J Intern Med 2017

13. Over view on different proteins involving
in cell cycle regulation
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Tobias Otto et al ; Cell cycle proteins as promising targets in cancer therapy ,nature reviews, 2017

14. Cell cycle checkpoints
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15. G1 phase checkpoint
 G1 be divided into 2 portions: G1-pm for G1-postmitotic, and G1-ps for G1-pre-S
 Whereas G1-pm is relatively constant, G1-ps is variable, and it is this variability in
the duration of G1-ps that contributes to much of the confusion.
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G1 cell cycle control / Foster et al. 2016

16. Contd….
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Foster et al G1 cell cycle control . 2016

17. G2 check point
 The G2 checkpoint is an intricate signaling network that
regulates the progression of G2 to mitosis (M)
 A node-based model of G2 checkpoint regulation, in which
the action of the central CDK1–cyclin B1 node is
determined by the concerted but opposing activities of the
Wee1 and cell division control protein 25C (CDC25C) nodes
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M. C. de Gooijer et al. G2 checkpoint switch; 2017

18. Contd…
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M. C. de Gooijer et al. G2 checkpoint switch; 2017

19. M phase check point
 During mitosis and meiosis, the spindle assembly checkpoint acts to
maintain genome stability by delaying cell division until accurate
chromosome segregation can be guaranteed.
 Accuracy requires that chromosomes become correctly attached to the
microtubule spindle apparatus via their kinetochores.
 When not correctly attached to the spindle, kinetochores activate the
spindle assembly checkpoint network, which in turn blocks cell cycle
progression.
 Once all kinetochores become stably attached to the spindle, the
checkpoint is inactivated, which alleviates the cell cycle block and thus
allows chromosome segregation and cell division to proceed.
Pablo Lara-Gonzalez et al The Spindle Assembly Checkpoint; 2012
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20. spindle assembly checkpoint-SAC
• The SAC is the most important mechanism of the mitotic phase, and
it ensures that anaphase will not occur until the chromosomes are
correctly aligned at the equatorial plate
• In this sense, cell cycle regulators such as the CDK1-cyclin B
complex are important components of SAC
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Larissa Siqueira Penna et al Anti-mitotic agents;2017

21. Anti mitotic agents
 Mitotic phase targeting disturbs mitosis in tumor cells, triggers the spindle
assembly checkpoint and frequently results in cell death
 The first antimitotics to enter clinical trials aimed to target tubulin.
Although these drugs improved the treatment of certain cancers, and
many anti-microtubule compounds are already approved for clinical use,
severe adverse events such as neuropathies were observed
 Since then, efforts have been focused on the development of drugs that
also target kinases, motor proteins and multi-protein complexes involved
in mitosis
Larissa Siqueira Penna et al Anti-mitotic agents;2017
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22. Anti mitotic agents
S. no protein Targeting agents
1 AURKA and AURKB Danusertib, AT9283, Barasertib,
Alisertib, ENMD-2076, PF-03814735
2 CDK1 P276-00, Terameprocol, Seliclib,
Dinaciclib
3 Tubulin Vinflunine, ABT-751, Tesetaxel,
Patupilone, Sagopilone, Vintafolide, TPI
287
4 EG5 Ispinesib, Filanesib, MK-0731, SB743921
5 26S Proteasome Delanzomib
6 PLK1 Volasertib, GSK 461364
7 CENP-E GSK-923295, Lonafarnib
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Larissa Siqueira Penna et al Anti-mitotic agents;2017

23. Summary
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•The abnormal expression of cell cycle regulators (activators and
inhibitors) can cause alteration of cell division leads to different types of
cancer
•As we known checkpoints plays a important role in cell cycle
progression through all the phases, it is novel target to treat many of
cancers

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Thank you