slide show on cell cycle

3.  CELL CYCLE
 A precisely programmed series of events that enables a cell to
duplicate its contents and to divide into two daughter cells
 The phases of cell cycle
 G1, S , G2, and M.
 A fifth stage - G0 - the resting, non proliferating state of cells
that have withdrawn from the active cell cycle.

4. • There are three stages of interphase: G1 , S and G2
• Cells spend most of their lives in interphase
• G1 phase - cell growth , protein synthesis
• S phase - DNA and centrosomes are replicated
• G2 phase - energy replenishment , mitotic specific proteins
synthesis, cytoskeleton dismantling and additional growth

5. Image Source - le.ac.uk/vgec/topics/cell-cycle/the-cell-cycle-schools-and-colleges

7. • During the PROPHASE of mitosis,
the chromosomes , which were
invisible microscopically during
interphase , begin to condense
and become visible, while the
centrosomes at the poles of the
cell begin to assemble .
• During METAPHASE , the
chromosomes align along a plane
that bisects the cell and become
attached to the microtubule
fibers of the mitotic spindle . At
the same time, the nuclear
membrane has disappeared.
Image source - cellular division- Jayant , Meyers, Geddis,and Priano (2014)

8. • During ANAPHASE , the
chromatids are pulled apart by
the mitotic spindle to the
opposite poles of the cell
• During TELOPHASE, shortly after
the chromatids cluster into the
two sets , they de-condense and
a new nuclear membrane forms
around each set of chromatids .
At the same time, during the
process of cytokinesis, the
cytoplasm of the mother cell
divides, yielding two daughter
cells.
Image source - cellular division- Jayant , Meyers, Geddis,and Priano (2014)

10. CELL CYCLE CLOCK
• A network of interacting proteins—a signal-processing circuit—that decides
the cell’s fate.
Image source - The biology of cancer Robert A. Weinberg

11. • Cyclins and cyclin-dependent kinases constitute the core components of the
cell cycle clock
• Cyclins undergo cyclical changes in their concentration which depends on the
transcription of its gene and by the degradation of subsequent regulated
proteins
• The concentration of CDKs doesn’t fluctuate
• Cyclin & CDK exert their effect by phosphorylating the target proteins
• Dephosphorylation is an important mechanism for resetting the cell for another
round of the cell cycle.

13. Image source - The biology of cancer Robert A. Weinberg

14. source - The biology of cancer Robert A. Weinberg

15. • Signaling pathways that sense and induce a cellular response to DNA
damage.
• The components are DNA damage sensors, signal transducers, or
effectors.
• A decatenation checkpoint in late G2 prevents entrance into M until the
pair of DNA helices replicated in the previous S phase have been
untangled from one another.
• Disruption of checkpoint function leads to genomic and chromosomal
instability leading to mutations that can induce carcinogenesis

17. • CDKs are serine/ threonine kinases - sequentially regulate progression of
cell through the cell cycle via phosphorylation.
• 4 mechanisms of CDK regulation :-
- Association with cyclins
- Association with CDK inhibitors
- Addition of phosphate groups that activate CDK activity
- Addition of phosphate groups that inhibit CDK activity
• Regulators of the cell cycle are required because of the precise window of
time and hence ‘disappearance’ of a factor is as important as its
‘appearance’.

18. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

19. ASSOCIATION WITH CYCLINS
• The binding of cyclins to their partner cdk causes a conformational
change in the cdk and this allows binding of a protein substrate and
correct positioning of ATP.
• Some cyclins increases the affirnity of cdks to specific substrates.
• The amounts of cyclin protein vary through the cell cycle that are
modified by transcriptional regulation of the cyclin genes and by protein
degradation
• The ubiquitinization of cyclins induces its degradation by the proteasome
which prevents further activity of cdks.

20. ASSOCIATION WITH INHIBITORS
• 2 Families of inhibitors are involved in regulating cyclin–cdk activity:
- p16 INK 4a family
- p21 Cip/Kip family
• INK Protein binds to cdk 4/6 and interferes with its binding to cyclin D
• Cip/Kip family of inhibitors interact with both cyclins and their associated
cdks (mainly with cdk2 and cyclin E) and disable kinase activity.
• Mitogenic stimulation followed by cyclin D synthesis , corresponding cdk
sequester inhibitors of the cip /kip family facilitates the cyclin E –cdk 2
activation
• ubiquitin-mediated degradation of inhibitors ensures that the inhibitors
are present during a specific period of time during the cell cycle.

21. REGULATION BY PHOSPHORYLATION
• This involves both activation and inhibition.
• Two phosphorylation sites on the amino-terminal end are inhibitory when
phosphorylated
• tyrosine kinase, wee1- phosphorylates Thr14 and Tyr1 which are located
deep within the ATP-binding site of the cdk and phosphorylation of these
sites physically interferes with ATP binding.
• Two steps are required for cdks to become active:
Dephosphorylation of the inhibitory phosphate groups by cdc25
phosphatases
Phosphorylation of a central threonine residue- Thr161 by cdk-activating
kinase (CAK).

22. source - The biology of cancer Robert A. Weinberg

23. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

24. • Blocks entry to M phase of those cells with DNA damage or those not
completing S phase
Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

25. • Activation of the G2 checkpoint results in the inhibition of Cdc25s by
Chk1/2.
• Specific Cdc25s (type B and C) are important in the G2–M phase
transition.
• DECATENATION G2 CHECKPOINT
- detangles intertwined daughter chromatids after DNA synthesis
- enables chromatid separation during anaphase of mitosis
- Topoisomerase II – releases tortional stress by breaking ds -DNA
to allow unwinding (key enzyme in decatenation check point)

26. • Also known as spindle assembly check point
• It is a signaling cascade that ensures correct chromosomal segregation
during mitosis and the production of two genetically identical nuclei.
• Unattached chromatid pairs attract inhibitors of Anaphase promoting
complexes
• Targets degradation proteins (securin)  separase sister chromatids
separation during anaphase
• APC inhibition stops after all chromatid pairs are attached to spindle fibres

27. Lauren Pecornio- Molecular biology of cancer -mechanisms, targets , and therapeutics 3rd edition (2012)

28. Sorce - Angius, G.; Tomao, S.; Stati, V.; Vici, P.; Bianco, V.; Tomao, F. Prexasertib, a checkpoint kinase inhibitor: From preclinical data to clinical development. Cancer Chemother. Pharmacol. 2020, 85, 9–20. [Google Scholar]
[CrossRef

29. source - The biology of cancer Robert A. Weinberg

30. source - The biology of cancer Robert A. Weinberg

31. Table - Basic and Clinical Pharmacology, 13th Ed. Cancer Chemotherapy Edward Chu, MD, & Alan C. Sartorelli, PhD
Image-www.amboss.com/us/knowledge/Chemotherapeutic_agents#anker=Zaf1779dab451b9a98d11834d04e33388