Cell cycle

Cell cycle

1. Cell Cycle and Its Control Mohammed Fathy Bayomy, MSc, MD Lecturer Clinical Oncology & Nuclear Medicine Faculty of Medicine Zagazig University

2. Cell Cycle

3. Series of events that take place in cell leading to its division & duplication (replication) Cell cycle can be divided in three periods: interphase—during which cell grows, accumulating nutrients needed for mitosis & duplicating its DNA & mitosis, during which cell splits itself into two distinct cells, often called "daughter cells" & final phase, cytokinesis, where new cell is completely divided Cell-division cycle is vital process by which zygote develops into mature organism, as well as process by which hair, skin, blood cells, & some internal organs are renewed Definition

4. Cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) & M phase (mitosis, cytokinesis) M phase is itself composed of two tightly coupled processes: mitosis, in which cell's chromosomes are divided between two sister cells, & cytokinesis, in which the cell's cytoplasm divides in half forming distinct cells. Activation of each phase is dependent on proper progression & completion of previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered state of quiescence called G0 phase Phases

5. After cell division, each of the daughter cells begin interphase of new cycle. Although various stages of interphase are not usually morphologically distinguishable, each phase of cell cycle has distinct set of specialized biochemical processes that prepare cell for initiation of cell division

6. 4 Cell division Mitosis 3 DNA repair G2 1 Cell grows, doubles in size G1 S 2 Chromosome duplication G2/M checkpoint G1/S checkpoint

7. INTERPHASE G 1 G 2 S (DNA synthesis) MITOTIC (M) PHASE Cytokinesis Mitosis

8. Term "post-mitotic" is sometimes used to refer to both quiescent & senescent cells Nonproliferative cells generally enter quiescent G0 state from G1 Some cells remain quiescent for long periods of time, possibly indefinitely (as is often case for neurons). This is very common for cells that are fully differentiated Some cells enter G0 phase semi-permanentally e.g., some liver & kidney cells Cellular senescence occurs in response to DNA damage or degradation that would make cell's progeny nonviable; it is often biochemical reaction; division of such cell could, for example, become cancerous. G0 Phase

9. Interphase Before cell can enter cell division, it needs to take in nutrients. All of preparations are done during interphase Interphase is series of changes that takes place in newly formed cell & its nucleus, before it becomes capable of division again It is also called preparatory phase or intermitosis Previously it was called resting stage because there is no apparent activity related to cell division Interphase proceeds in three stages, G1, S, G2 Preceded by previous cycle of mitosis & cytokinesis The most significant event is replication of genetic material (DNA) in S phase

10. G1 phase First phase within interphase, from end of previous M phase until beginning of DNA synthesis, is called G1 (G indicating gap) It is also called growth phase During this phase biosynthetic activities of cell, which are considerably slowed down during M phase, resume at high rate This phase is marked by use of 20 amino acids to form millions of proteins & later on enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of same species It is under control of p53 gene

11. S phase S phase starts when DNA replication occur When it is complete, all of chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids During this phase, amount of DNA in cell has effectively doubled, though ploidy of cell remains same. During this phase, synthesis is completed as quickly as possible due to exposed base pairs being sensitive to external factors such as any drugs taken or any mutagens

12. G2 phase Gap between DNA synthesis and mitosis Cell will continue to grow G2 checkpoint control mechanism ensures that everything is ready to enter M (mitosis) phase & divide

13. Interphase Before cell can enter cell division, it needs to take in nutrients. All of preparations are done during interphase Interphase is series of changes that takes place in newly formed cell & its nucleus, before it becomes capable of division again It is also called preparatory phase or intermitosis Previously it was called resting stage because there is no apparent activity related to cell division Interphase proceeds in three stages, G1, S, G2 Preceded by previous cycle of mitosis & cytokinesis The most significant event is replication of genetic material (DNA) in S phase

14. M phase Consists of karyokinesis & cytokinesis Mitosis is process by which cell separates chromosomes in its cell nucleus into two identical sets in two nuclei: during process of mitosis pairs of chromosomes condense & attach to fibers that pull sister chromatids to opposite sides of cell, followed immediately by cytokinesis, which divides nuclei, cytoplasm, organelles & cell membrane into two cells containing roughly equal shares of these cellular components

15. Mitosis & cytokinesis together define mitotic (M) phase of cell cycle - division of mother cell into two daughter cells, genetically identical to each other and to their parent cell This accounts for approximately 10% of cell cycle Sequence of events is divided into phases * Prophase * Metaphase * Anaphase * Telophase * Cytokinesis (part of M phase, not part of mitosis)

16. State Description Abbreviation Quiescent/ Senescent Gap 0 G0 Resting phase where cell has left cycle & has stopped dividing Interphase Gap 1 G1 Cells increase in size in Gap 1. G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis Synthesis S DNA replication occurs during this phase Gap 2 G2 During gap between DNA synthesis & mitosis, cell will continue to grow. G2 checkpoint control mechanism ensures that everything is ready to enter M (mitosis) phase & divide Cell division Mitosis M Cell growth stops at this stage & cellular energy is focused on orderly division into two daughter cells. checkpoint in middle of mitosis (Metaphase Checkpoint) ensures that cell is ready to complete cell division

17. Stages of Mitosis

18. Chromosomes Chromosomal DNA molecules Centromere Chromosome arm 1

19. Chromosomes Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication (including DNA replication) and condensation Sister chromatids 1 2

20. Chromosomes Chromosomal DNA molecules Centromere Chromosome arm Chromosome duplication (including DNA replication) and condensation Sister chromatids Separation of sister chromatids into two chromosomes 1 2 3

21. Cell Cycle Control

22. Major players Cyclins cdk (cyclin – dependent kinases) MPF ( M aturation P romoting F actor) = cyclin B- cdk1 kinase (“mitotic cdk ”) CAK ( C dk A ctivating K inases) regulators of cdks CKI – cdk inhibitory subunits APC ( A naphase P romoting C omplex) cdc34/SCF ubiquitination pathways which activate proteolysis via proteosomes

23. * Definition: family of proteins that activate cyclin-dependent kinase ( Cdk ) enzymes * Include: cyclin A, cyclin B, cyclin D, cyclin E Cyclins

24. * Definition: family of protein kinases have role in regulating cell cycle * Include: cdk1, cdk2, cdk4, cdk6 Cyclin – dependent kinases

25. Cyclins Cyclin dependent kinases (cdks) Cdk1 Cyclin D G1 Cyclin E Cyclin A S Cdk4,6 Cdk2 Cyclin A Cyclin B M

26. * Definition: heterodimeric protein composed of cyclin B & cyclin-dependent kinase (CDK1) * Function: promotes entrance into mitosis (M phase) from G2 phase by phosphorylating multiple proteins needed during mitosis Maturation Promoting Factor

27. * Function: activates cyclin-CDK complex by phosphorylation. CAK itself is member of the Cdk family & functions as positive regulator of Cdk1, Cdk2, Cdk4, Cdk6 Cdk Activating Kinases

28. * Definition: protein which inhibits cdK * Two families - cip /kip family: p21, p27 & p57 - INK4a/ARF family: p16INK4a, p19ARF cdk inhibitory subunits

29. * Definition: E3 ubiquitin ligase that marks target cell cycle proteins for degradation by 26S proteasome Anaphase Promoting Complex

30. APC cdk1 Cyclin B Fzr Fzy Anaphase cdc14 P P P P P P P

31. Sister chromatid separation from prometaphase to anaphase Securin Separase Cohesin metaphase Securin Separase Cohesin prometaphase APC Check point Ub Ub Ub Separase APC Separase anaphase Check point

32. * Definition: Skp , Cullin , F-box containing complex (or SCF complex) is a multi-protein E3 ubiquitin ligase complex catalyzing ubiquitination of proteins destined for proteasomal degradation. It has important roles in ubiquitination of proteins involved in cell cycle & also marks various other cellular proteins for destruction cdc34/SCF Pathway

33. G 1 checkpoint G 1 G 2 G 2 checkpoint M checkpoint M S Control system

34. G 1 checkpoint G 1 G 1 G (a) Cell receives go-ahead signal (b) Cell does not receive a go-ahead signal

35. P Cyc D cdk4 pRB E2F E2F E2F E2F P P P P E2F E2F E2F E2F Cyc E cdk2 S G1