Cell cycle and growth regulation

Cell cycle and growth regulation and functional relevance to perioontitis

1. Cell cycle and Growth regulation By Archana. B Ist yr PG

2. Cell is the fundamental structural and functional unit of all living organisms . Anton Von Leeuwenhoek first saw and described a live cell. Robert Brown later discovered the nucleus. The invention of the microscope and its improvement leading to the electron microscope revealed all the structural details of the cell .

3. Cell division is a very important process in all living organisms. During the division of a cell, DNA replication and cell growth also take place. All these processes, i.e., cell division, DNA replication, and cell growth, have to take place in a coordinated way to ensure correct division and formation of progeny cells containing intact genomes. The sequence of events by which a cell duplicates its genome, synthesi z es the other constituents of the cell and eventually divides into two daughter cells is termed cell cycle.

4. Phases of Cell Cycle The cell cycle is divided into two basic phases: Interphase M Phase (Mitosis phase) The interval between the mitotic phase is called interphase and the non- dividing cells spend most of their lifetime in this phase. The M Phase starts with the nuclear division, corresponding to the separation of daughter chromosomes ( karyokinesis ) and usually ends with division of cytoplasm ( cytokinesis ).

5. The interphase, though called the resting phase, is the time during which the cell is preparing for division by undergoing both cell growth and DNA replication in an orderly manner. The interphase is divided into three further phases: G 1 phase (Gap 1) S phase (Synthesis) G 2 phase (Gap 2) The cells that do not divide further remain in G1 phase to enter an inactive stage called quiescent stage (G ) of the cell cycle.

6. M Phase This is the most dramatic period of the cell cycle, involving a major reorganisation of virtually all components of the cell. Since the number of chromosomes in the parent and progeny cells is the same, it is also called as equational division. Mitosis is divided into the following four stages: Prophase Metaphase Anaphase Telophase

7. Chromatin condensation and nuclear membrane breakdown. Sister chromatids move to the equator Pro metaphase

8. Chromosomes line up Seperation of sister chromatids

9. Seperation of poles occurs and nuclear envelope forms cytokinesis

10. Functional relevance to periodontium: Periodontal tissues consists of several cell types and in various stages of activity. There is a constant need for the periodontal ligament and alveolar bone to under go remodelling.

11. When situation demands such as following load application there must be constant increase in the tissue turn over A large proportion of cells are in G phase in an un divided phase where they await instruction before they start dividing. When need arises external stimuli can induce cells to move from G to G 1 phase and there by contribute to increased tissue turnover.

12. Regulation of cell cycle

13. The cell cycle is not an un coordinated series of events that operate without any regulatory mechanism. Regulatory proteins control the rate of cell division by providing stops that can halt the cell cycles at specific check points. In addition there is a feed back signalling mechanism which functions to arrest or slowdown the processes that control the functioning of these regulatory proteins. INTRACELLULAR EVENTS: Regulation of cell cycle is achieved by two sets of proteins: Cycline dependent kinases (Cdk) Cyclines

14. The Cdk are proteins that phosphorylate select proteins at serine – threonine residues These phosphorylated proteins then donstream the signals that influence the cell cycle and there by the mitotic process is completed.

15. The other set of proteins that are associated with cell cycle are cyclines. They undergo cycle of synthesis and degradation during each cycle of the cell division. They act by binding to Cdk proteins and regulate their ability to phosphorylate target proteins. Two types of cyclines have been recognized Mitotic cyclines G 1 cyclines

16. Mechanism of action; Positive feedback mechanism End of metaphase and begining of anaphase

17. The mechanism of action of the G1 cyclins occur in a similar manner The difference occurs only at the level of their action The G1 cyclins bind to the Cdk at the G1 phase and target series of events that lead to DNA replication

18. Activation of Cdk proteins Although the mechanism of action of cyclines are similar the down stream signals are completely different The Cdk complexes that are phosphorylated in the two processes differ The substrate in each phase are phosphorylated in such a way that the activation of of one protein can influence one specific event

19. For the full activation of Cdk cyclin complex the cells require Cdk Activating Kinase (CAK) These enzymes activate aminoacids that are in close to the activation sites of Cdk proteins And thus the Cdk proteins become potent enough to phosphorylate other proteins that are involved in mitosis.

20. Other proteins involved in the cell cycle are: Cdk inhibitory proteins Cyclin proteolytic proteins

21. Cdk inhibitory proteins (Cdki) The Cdki bind to the Cdk protein and cause conformational change in the three dimensional structure of the protein The active sites of these protins are not free for further interaction and so the Cdk proteins are inactivated

22. Cyclin proteolytic proteins: Cyclin lysis: The proteolytic destruction of cyclin causes a stop to the cell cycle It occurs by a ubiquitin dependent mechanism Several ubiquitin are added to a specific amino acid sequence in the cyclin protein This allows the proteosomes to degrade the cyclines

23. This process if influenced by a protein called ubiqutin ligases namely SCF and APC SCF is present constantly through out the cell cycle and regulats the addition of ubiquitin APC is expressed only during certain stages in the cell cycle and are specifically involved in protelysis

24. Extracellular regulation: In the periodontium the cell cycle is regulated by external stimuli These stimuli of the periodontium majorly help in the cell division and keeps in pace with the demands of the extracellular matrix These stimuli are classified into 3 types Mitogens Growth factors Survival factors

25. Mitogens & Growth Factors : They assist the cells to divide more rapidly than normal Important mitogens that are involved in the periodontium are PDGF,EGF and IGF Target cells for these molecules are mesenchymal, epithelial and endothelial cells. These mitogens act chiefly by the activation of G1Cdk activity Activation of Cdk occur after the mitogens bind to the cell surface receptors and activate pathways like the MAPK pathway

26. These factors help in the cell growth as a result of upregulation of intercellular differentiation Some growth factors can also act as mitogens

27. Growth factor Receptors: They are a large group of trans membrane protein with more than 50 members Receptors are classified into two types Type 1 – N- terminal outside the cell and C- terminal inside the cytoplasm side Type 2- N – terminal on the cytoplasmic side

28. All growth factor receptors are type 1 Growth factors bind to the extra cellular N-terminal domain and the C terminal usually contain the kinase domain. The Receptors with kinase domain may have tyrosine or serine - threonine kinase activity or no kinase activity at all.

29. These receptors are responsible for mediating their targetted function and they bind to their ligands with high affinity Some growth factors like FGF and TGF β also bind to sites with lower affinity

30. Survival Factors: These proteins bind to the Bcl2 proteins and as a result of this binding – prolongs Apoptosis That avoids early cell death and increases cellular activity.

31. Various Pathways in periodontal cell signelling: WNT pathway Smad pathway MAPK pathway NF- κ B pathway

32. Cell Injury:

33. Cell Death: Tissue homeostasis is maintained by the ability of proliferating cells to synthesize macromolecules after differentiation Proliferation results in the formation of sufficient number of cell colonies that are required for adequate matrix synthesis. Unchecked prolferation would result in the far greater number of cells than that can be accomodated in the matrix.

34. Two major forms of cell death in humans are 1. Necrosis 2. Apoptosis

35. Necrosis: Coagulation Necrosis: This type of cell death occurs as a result of denaturation of protein with in the cell. Because of the breakdown of various components of the cell. They commonly are associated with external factors like heat , physical stress etc. Liquifactive necrosis: This type is commonly associated with release of hydrolytic and other digestive enzymes that cause cell destruction. This type of necrosis is seen in inflammatory conditions.

36. Regardless of the type of necrosis, this process is trigerred by factors that are present in the external environment of the cell triggers or activates destructive changes in the cell. It is a dominanat form of cell death seen during pathological changes that affect the cell due to infection.

37. Necrosis occurs in various periodontal diseases but the degree of necrosis varies in different forms of diseases. Necrotising periodontal disease have been cassified into Acute necrotisimg ulcerative gingivitis Necrotising ulcerative periodontitis. ANUG occurs as an infection resulting from spirochetes and fusobacterium when host related factors can aid this process features of ANUG is the formation of punched out creaters in the creast of the interdental papilla. Necrotizing ulcerative periodontitis is where the infection leads to attachment loss, but involves only the gingiva , periodontal ligament and alveolar bone. Usually this spectrum of diseases result in loss of attachment, and therefore many ANUG diagnoses may be technically termed NUP, although ANUG is the term in most common use.

38. Apoptosis: The cells of a multicellular organism are members of a highly organized community. The number of cells in this community is tightly regulated—not simply by controlling the rate of cell division , but also by controlling the rate of cell death. If cells are no longer needed, they commit suicide by activating an intracellular death program. This process is therefore called programmed cell death although it is more commonly called apoptosis .

39. Autophagy also kills the cells under certain conditions. These are form of programmed cell death (PCD) and are called autophagic cell death . Autophagy is termed a nonapoptotic programmed cell death with different pathways and mediators from apoptosis. It mainly maintains a balance between manufacture of cellular components and break down of damaged or unnecessary organelles and other cellular constituents. There are some major degradative pathways that include proteasome that involves breaking down of most short-lived proteins.

40. CONCLUSION Cell cycle is an important biological phenomenon that controls the proliferative activity of cells . Proliferation is an important part of wound healing and repair and an important parameter that needs to be assessed in pathologies that involve aberrent healing. Periodontitis eventually occurs as a result of an imbalance between the invading micro- organisms and the host response Proliferative activity as assessed by te estimation of cellcycle may reflect the state of the pathological as well as the healing processes in the periodontium.

41. REFERENCES: Text book of Biology NCERT Molecular biology of periodontium– Dr. K.V. Arun Text book of molecular biology- Dr. Sampathnarayanan Online reference: Khan’s Acadamy