cell growth, division and apoptosis.pptx

The presentation explains the CELL growth and Cell Division Cycles.
Cell growth comprises of four phases G1 phase or gap phase, Sphase or synthesis pHase and G2 phase or gap2 Phase, M phase or mitotic phase. Cell grows during g1 phase, DNA replicates in S phase, DNA multiplies but chromosome number remains Same in G2 phase and cell growth also takes place and MPhase marks the division of cell - karyokinesis and cytokinesis.

When the cell cycle is disrupted or isnt controlled Cancer or tumourous growth of cell takes place.

The cell itself have a controlled death called apoptosis.
When cell growth, cell division and apoptosis take place in regualated manner, cell cycle takes place accurately.
The factors required For Cell Growth.
CELL DEATH CAUSED BY APOPTOSIS - intrinsic and Extrinsic pathway.
CANCER Cell Cycle.
These are major topics of molecular biology and cell biology for bachelors and postgraduate studies of lifescience subjects.
These are also important topics of other Competitve Exams.

1. Control Of Cell Division And Cell Growth, Regulation Of Cell Cycle In Malignant Cells, Apoptosis : Extrinsic And Intrinsic Pathways, Significance Of Apoptosis Submitted By : Hridya S Pillai Christian College Chengannur

2. Cell Growth and cell Division Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also its mass. The growth of a cell consists of the uptake of nutrients as well as water across the cell membrane. Metazoan cell growth was found to depend not only on nutrients, but also on cell-cell communication, namely growth signaling molecules, and cell-cell contact Some of these nutrients become building blocks of macromolecules, such as proteins and nucleic acids, which form large complexes having negligible influence on the osmolarity of the intracellular environment, whereas other nutrients remain solvated.  Growth factor signaling, is also a prerequisite for cell cycle progression in most types of cells. growth signaling activates the transcription of G1 Cyclin genes to induce cell proliferation and also stimulates anabolic metabolism and cell growth in parallel,

3. To divide , the cell goes through a process called the cell cycle . There are four main stages or phases. Gap 1 or G1 phase , where the cell grows in size , and checks that everything is OK for it to divide. Synthesis or the  S phase , where the cell copies its DNA .  Gap 2 or G2 phase , where the cells check that all its DNA has been correctly copied. Mitosis or M phase , where the cell finally divides in two . During mitosis , the cell shares the copied DNA equally between the 2 new cells. This means that the cell separates  all the copied chromosomes into 2 full sets . The other material that makes up the cell also splits in two. The result is two identical daughter cells. Growth and division do not necessarily proceed in synchrony, as division may occur without growth, and growth without division. These two mechanisms are regulated independently and it is understood that cell growth does not depend on cell-cycle progression. Nevertheless, some coordination usually occurs, whereby proliferation and growth produce cells whose size remains unchanged over consecutive generations

4. Organ and body size are determined by three fundamental processes: cell growth, cell division, and cell death Each is tightly regulated-both by intracellular programs and by extracellular signal molecules that control these programs. The extracellular signal molecules that regulate cell size and cell number are generally soluble secreted proteins, proteins bound to the surface of cells, or components of the extracellular matrix. They can be divided operationally into three major classes: . Mitogens, which stimulate cell division, primarily by triggering a wave of Gr/S- Cdk activity that relieves intracellular negative controls that otherwise block progress through the cell cycle. . Growth factors , which stimulate cell growth (an increase in cell mass) by promoting the synthesis of proteins and other macromolecules and by inhibiting their degradation . . survival factors , which promote cell survival by suppressing the form of programmed cell death known as apoptosis. Many extracellular signal molecules promote all of these processes.

5. Control Of Cell Division And Cell Growth There are extracellular signal molecules that suppress cell proliferation, cell growth, or both. There are also extracellular signal molecules that activate apoptosis. Mitogens and other factors, such as DNA damage, control the rate of cell division. A proliferating cell coordinates its growth with cell division so as to maintain its appropriate size.

6. Mitogens Stimulate Cell Division The cells of a multicellular organism divide when the organism needs more cells. For an animal cell to proliferate, it must receive extracellular signal in the form of mitogens from other cells. Mitogens overcome intracellular mechanisms that block progress through the cell cycle. One of the first mitogens to be identified was the platelet derived growth factor. In the body PDGF liberated from blood clots helps stimulate cell division during wound healing. PDGF is only one over 50 proteins that are known to act as mitogens. PDGF can stimulate many cell types to divide including fibroblast, smooth muscle cells and neuroglia cells . Epidermal growth factor acts on epidermal epithelial and non epithelial cells . Erythropoietin induces proliferation of only red blood precursors . Mitogens can also stimulate cell growth, survival differentiation or migration .

7. TGF β In some tissues inhibitory extracellular signal proteins oppose the positive regulators and thereby inhibit organ growth . The best understood inhibitory signal proteins are TGF β and its relatives. TGF β inhibits the proliferation of several cell types, either by blocking cell-cycle progression in G1 or by stimulating apoptosis

8. Cells Can Delay Division by Entering a Specialized Non-dividing State In the absence of a mitogenic signal to proliferate, Cdk inhibition in G1 is maintained by the multiple mechanisms, and progression into a new cell cycle is blocked. In some cases, cells partly disassemble their cell-cycle control system and exit from the cycle to a specialized, non dividing state called G0. Most cells in our body are in G0, but the molecular basis and reversibility of this state vary in different cell types. Most of our neurons and skeletal muscle cells, for example, are in a terminally differentiated G0 state, in which their cell-cycle control system is completely dismantled. The expression of the genes encoding various Cdks and cyclins are permanently turned off, and cell division rarely occurs. Almost all the variation in cell-cycle length in the adult body occurs during the time the cell spends in G1 or Go. By contrast, the time a cell takes to progress from the beginning of S phase through mitosis is usually brief (typically 12-24 hours in mammals) and relatively constant, regardless of the interval from onedivision to the next

9. Mitogens Stimulate G1-Cdk and G1/S- Cdk Activities Mitogens control the rate of cell division by acting in the G1 phase of the cell cycle. Multiple mechanisms act during G1 to suppress Cdk activity and thereby block entry into S phase. Mitogens release these brakes on Cdk activity, thereby allowing S phase to begin. They interact with cell-surface receptors to trigger multiple intracellular signaling pathways. One major pathway acts through the small GTPase Ras , which leads to the activation of a MAP kinase cascade. This leads to an increase in the production of gene regulatory proteins, including Myc. Myc is thought to promote cell-cycle entry by several mechanisms, one It increase the expression of genes encoding G1 cyclins (D cyclins), thereby increasing G1 - Cdk (cyclin D- Cdk4) activity.

10. Myc also has a major role in stimulating the transcription of genes that increase cell growth. The key function of g1-cdk complexes in animal cells is to activate a group of gene regulatory factors called the E2F proteins. E2F Proteins binds to specific DNA sequences in the promoters of a wide variety of genes that encode proteins required for S-phase entry. Including G1/S-cyclins, S-cyclins, and proteins involved in DNA synthesis and chromosome duplication. In the absence of mitogenic stimulation, e2f-dependent gene expression is inhibited by an interaction between e2f and members of the retinoblastoma protein ( Rb ) family.

11. DNA Damage Blocks Cell Division: The DNA Damage Response The cell-cycle control system can readily detect DNA damage . Arrest the cycle at either of two checkpoints- One at start in late G1, which prevents entry into the cell cycle and into S phase, One at the G2/M checkpoint, which prevents entry into mitosis DNA damage initiates a signaling pathway by activating one of a pair of related protein kinases called ATM and ATR. Which associate with the site of damage and phosphorylate various target proteins, including two other protein kinases called chk l and chk 2. Together these various kinases phosphorylate other target proteins that lead to cell-cycle arrest .

12. A major target is the gene regulatory protein p53 , which stimulates transcription of the gene encoding a CK I protein called p21. this protein binds to G1/S- Cdk and S- Cdk complexes and inhibits their activities , thereby helping to block entry into the cell cycle. DNA damage activates p53 by an indirect mechanism . In undamaged cells, p53 is highly unstable and is present at very low concentrations. This is largely because it interacts with another protein, Mdm2 , which acts as a ubiquitin ligase that targets p53 for destruction by proteasomes. Phosphorylation of p53 after DNA damage reduces its binding to Mdm2 . This decreases p53 degradation , which results in a marked increase in p53 concentration in the cell . In addition, the decreased binding to Mdm2 enhances the ability of p53 to stimulate gene transcription.

13. The protein kinases Chk 1 and Chk 2 also block cell cycle progression by phosphorylating members of the Cdc25 family of protein phosphatases , thereby inhibiting their function. the inhibition of cdc25 activity by DNA damage helps block entry into mitosis .

14. The DNA-damage response also detects problems that arise when a replication fork fails during DNA replication. To prevent the cell from attempting to segregate partially replicated chromosomes, the same mechanisms that respond to DNA damage detect the stalled replication forks and block entry into mitosis until the problems at the replication fork are resolved. Cells that divide with severe DNA damage threaten the life of the organism, since genetic damage can often lead to cancer and other diseases. Thus, animal cells with severe DNA damage do not attempt to continue division, but instead commit suicide by undergoing apoptosis. DNA damage-induced apoptosis often depends on the activation of p53.

15. Many Human Cells Have a Built-ln Limitation on the Number of Times They Can Divide Many human cells divide a limited number of times before they stop and undergo a permanent cell-cycle arrest . Toward the end of this time, proliferation slows down and finally halts and the cells enter a non dividing state from which they never recove r. This phenomenon is called replicative cell senescence , Replicative cell senescence in human fibroblasts seems to be caused by changes in the structure of the telomeres . Telomerase also promotes the formation of protein cap structures that protect the chromosome ends. human somatic cells, are deficient in telomerase, their telomeres become shorter with every cell division , and their protective protein caps progressively deteriorate. Eventually, the exposed chromosome ends are sensed as DNA damage , which activates a pS3-dependent cell-cycle arrest that resembles the arrest caused by other types of DNA damage.

16. most cancer cells have regained the ability to produce telomerase and therefore maintain telomere function as they proliferate; as a result, they do not undergo replicative cell senescence

17. Cell Growth Factors : growth of organ and organism cell growth and cell proliferation depend on extracellular signal molecules, produced by other cells, which we call growth factors and mitogens. Like mitogens, the extracellular growth factors that stimulate animal cell growth bind to receptors on the cell surface and activate intracellular signaling pathways. These pathways stimulate the accumulation of proteins and other macromolecules, and they do so by both increasing their rate of synthesis and decreasing their rate of degradation. They also trigger increased uptake of nutrients and production of the ATP required to fuel increased protein synthesis.

18. one of the most important intracellular signaling pathways activated by growth factor receptors involves the enzyme PI 3-kinase, which adds a phosphate from ATP to the 3 position of inositol phospholipids in the plasma membrane. the activation of PI 3-kinase leads to the activation of a kinase called TOR, which lies at the heart of growth regulatory pathways in all eukaryotes. TOR activates many targets in the cell that stimulate metabolic processes and increase protein synthesis. one target is a protein kinase called S6 kinase (S6K), which phosphorylates ribosomal protein 56,. increasing the ability of ribosomes to translate a subset of mRNAs that mostly encode ribosomal components. TOR also indirectly activates a translation initiation factor called eIF4E and directly activates gene regulatory proteins that promote the increased expression of genes encoding ribosomal subunits

19. APOPTOSIS Cell division exactly balances the cell death. Normal cells activate an intracellular cell death programme and kill themselves in a controlled way. This process is known as programmed cell death . The programmed cell death in animals usually but not exclusively, occurs by apoptosis. Biologists often use the terms programmed cell death and apoptosis interchangeably. Cells undergoing apoptosis undergo characteristic morphological changes . They shrink and condense, cytoskeleton collapses, nuclear envelope disassembles, and the nuclear chromatin condenses and breaks up into fragments . the cell surface often blebs and if the cell is large, often break up into membrane enclosed fragments called apoptotic bodies. Most importantly, the surface of the cell or apoptotic bodies becomes chemically altered so that a neighboring cell or macrophage rapidly engulfs them before they can spill their contents. In this way, the cell die neatly and is rapidly cleared away, without causing a damaging inflammatory response.

20. Proteolytic cascade that is mediated by caspases. The intracellular machinery responsible for apoptosis is similar in all animal cells. It depends on a family of proteases that have a cysteine at their active site and cleave their target proteins at specific aspartic acids . They are therefore called caspases. Caspases are synthesized in the cell as procaspases ( inactive precursors). these are activated by proteolytic cleavage. This cleavage occurs at one or two specific aspartic acids and is catalyzed by other active caspases . The procaspases are split into heterodimers ( one large and one small subunit). Two such heterodimers assembles to form a tetramer . Once activated, caspases cleave and thereby activate other procaspases , resulting in amplifying proteolytic cascade.

21. some of the procaspases that operate in apoptosis act at the start of the proteolytic cascade and are called initiator procaspases ; when activated, they cleave and activate downstream executioner procaspases , which, then cleave and activate other executioner procaspases as well as specific target proteins in the cell . Among the many target proteins cleaved by executioner caspases are the nuclear lamins , the cleavage of which causes the irreversible breakdown of the nuclear lamina . Another target is a protein that normally holds the DNA-degrading enzyme, endonuclease in an inactive form; its cleavage frees the endonuclease to cut up the DNA in the cell nucleus . Other target proteins include components of the cytoskeleton and cell-cell adhesion proteins that attach cells to their neighbors; the cleavage of these proteins helps the apoptotic cell to round up and detach from its neighbors, making it easier for a healthy neighboring cell to engulf it, or, in the case of an epithelial cell, for the neighbors to extrude the apoptotic cell from the cell sheet

22. The caspase cascade is not only destructive and self-amplifying but also irreversible , once a cell reaches a critical point along the path to destruction, it cannot turn back. The caspases require for apoptosis vary depending on the cell type and stimulus . The two best understood signaling pathways that can activate a caspase cascade leading to apoptosis in mammalian cells are called the extrinsic pathway and the intrinsic pathway . Each uses its own initiator procaspases and activation complex

23. Extrinsic pathway Extracellular signal proteins binding to cell-surface death receptors trigger the extrinsic pathway of apoptosis. death receptors trigger the extrinsic pathway of apoptosis is the activation of Fas on the surface of a target cell by Fas ligand on the surface of a killer (cytotoxic) lymphocyte . When activated by the binding of Fas ligand, the death domains on the cytosolic tails of the Fas death receptors recruit intracellular adaptor proteins, which in turn recruit initiator procaspases (procaspase-8, procaspase-10, or both), forming a death-inducing signaling complex (DISC). Once activated in the DISC, the initiator caspases activate downstream executioner procaspases to induce apoptosis Death receptors are transmembrane proteins containing an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular death domain , which is required for the receptors to activate the apoptotic program. The receptors are homotrimers and belong to the tumor necrosis factor (TNF) receptor family, which includes a receptor for TNF itself and the Fas death receptor . Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

24. Extrinsic pathway

25. Intrinsic pathway Cells activate their apoptosis program from inside the cell, usually in response to injury or other stresses, such as DNA damage or lack of oxygen, nutrients, or extracellular survival signals . Some of the released proteins activate a caspase proteolytic cascade in the cytoplasm, leading to apoptosis. A crucial protein released from mitochondria in the intrinsic pathway is cytochrome c, a water-soluble component of the mitochondrial electron-transport chain. When released into the cytosol , it has an entirely different function: it binds to a procaspase-activating adaptor protein called Apaf 1 (apoptotic protease actuating factor-l), This causes the Apaf 1 to oligomerize into a wheel-like heptamer called an apoptosome . The Apaf 1proteins in the apoptosome then recruit initiator procaspase proteins (procaspase-9), which are activated by proximity in the apoptosome, just as procaspase-8 and -10 proteins are activated in the DISC. The activated caspase-9 molecules then activate downstream executioner procaspases to induce apoptosis.

26. Intrinsic pathway

27. In some cells, the extrinsic pathway must recruit the intrinsic pathway to amplify the apoptotic signal to kill the cell. It does so by activating a member of the bcl2 family of proteins The intrinsic pathway of apoptosis is tightly regulated to ensure that cells kill themselves only when it is appropriate. A major class of intracellular regulators of apoptosis is the Bcl2 family of proteins, Bcl2 proteins regulate the intrinsic pathway by controlling the release of cytochrome c and other intermembrane mitochondrial proteins into the cytosol. Some Bcl2 proteins are pro-apoptotic and promote apoptosis by enhancing the release , whereas others are anti-apoptotic and inhibit apoptosis by blocking the release . The pro-apoptotic and anti apoptotic Bcl2 proteins can bind to each other in various combinations to form heterodimers, in which the two proteins inhibit each other's function. The balance between the activities of these two functional classes of Bcl2 proteins largely determines whether a mammalian cell lives or dies by the intrinsic pathway of apoptosis.

28. Three classes of Bcl2 proteins

29. Significance Of Apoptosis In animal development, apoptosis eliminates unwanted cells Cell death helps sculpt hands and feet during embryonic development: they start as spade like structures. Cells die when the structure they form is no longer needed : tadpole changes into frog by metamorphosis.(Cells in the tail die). Cell death helps regulate cell numbers . In developing nervous system, cell death adjusts the number of nerve cells to match the number of target cells that nerve cells connects to. It also functions as the quality-control process in development, eliminating cells that are abnormal, misplaced non functional or potentially dangerous to the animal . In Vertebrate adaptive immune system, apoptosis eliminates developing T and B lymphocytes that either fail to produce potentially useful antigen- specific receptors.

30. It also eliminates most of the lymphocytes activated by an infection after they have helped destroy the responsible microbes. In adult tissues that are neither growing nor shrinking , cell death and cell division must be tightly regulated to ensure they are in exactly in balance. Apoptosis occurs in staggeringly high rate in adult human bone marrow . Neutrophils are produced continuously in very large numbers but vast majority die in the bone marrow without ever functioning. This serves to maintain a ready supply of neutrophils to fight infection . DNA damage can produce cancer promoting mutations if not repaired. Cells have various ways of detecting DNA damage and if they cannot repair it, they often kill themselves by undergoing apoptosis.

31. REFERENCES https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418607/ (mechanics of cell growth) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193172/ (Cell growth and the cell cycle: New insights about persistent questions https://www.cancerresearchuk.org/about-cancer/what-is-cancer/how-cancer-starts/how-cells-and-tissues-grow Harvey Lodish , Arnold Berk, Paul Matsudaira , Chris A. Kaiser, Monty Krieger, Matthew P. Scott, Lawrence Zipursky , James Darnell - Molecular Cell Biology -W. H. Freeman (2008) Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter - Molecular Biology Of The Ce ll-Garland Science (2007)