apoptosis.pdf, Pr0grammed cell death - PCD

1. Apoptosis Programmed Cell Death Oleg Zalizniak (ramaloke.bgu@gmail.com) Igor Shulov Department of Nuclear Engineering Ben Gurion University Radiobiology, 2006/I Typeset by L ATEX

2. Introduction Functions Apoptotic process Implication in disease References Cell death types There are two cell death types: Programmed cell death (PCD) and Necrosis PCD has been classified into two main types: Apoptosis (or Type I cell death), is a particular form of programmed cell death and is described in this presentation. Autophagic (a.k.a. cytoplasmic, or Type II) cell death, characterized by the formation of large vacuoles that eat away organelles in a specific sequence before the nucleus is destroyed. Oleg Zalizniak, Igor Shulov BGU Apoptosis

6. Introduction Functions Apoptotic process Implication in disease References Introduction Figure: Cell cycle Apoptosis (a term derived from the Greek word describing the falling off of petals from a flower or leaves from a tree) is one of the main types of programmed cell death (PCD) Apoptotic process is executed in such a way as to safely dispose of cell corpses and fragments. Apoptosis plays complementary but opposite role to mitosis in the regulation of animal cell population. Oleg Zalizniak, Igor Shulov BGU Apoptosis

9. Introduction Functions Apoptotic process Implication in disease References Apoptosis vs Necrosis Apoptosis Necrosis Energy dependent PCD, cell die as result of damage DNA defragmentation (chemical, thermal, radiation,. . . ) one cell group of cells several hours hours to days membrane integrity intact membrane integrity faulty no inflammation acute inflammation Dead cells eaten by neighbour Dead cells removed by cells or macrophages macrophages (phagocytosis) Oleg Zalizniak, Igor Shulov BGU Apoptosis

15. Introduction Functions Apoptotic process Implication in disease References Functions of apoptosis Figure: Cell division: A - normal (1 - apoptosis, 2 - damaged cell); B - cancer Cell damage or infection. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis (tumour-suppressing gene p53). if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour. Oleg Zalizniak, Igor Shulov BGU Apoptosis

18. Introduction Functions Apoptotic process Implication in disease References Homeostasis Homeostasis (balance between cell born and die) is achieved when the rate of mitosis (cell proliferation) in the tissue is balanced by cell death. If this equilibrium is disturbed, one of two potentially fatal disorders occurs: The cells are dividing faster than they die, effectively developing a tumor. The cells are dividing slower than they die, which results in a disorder of cell loss. Between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. In a year, this amounts equal to an individual’s body weight. Oleg Zalizniak, Igor Shulov BGU Apoptosis

19. Introduction Functions Apoptotic process Implication in disease References Development Figure: Incomplete differentiation in two toes due to lack of apoptosis Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell, with the resultant mass is then “pruned” into the correct form by apoptosis. Apoptosis allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances into the surrounding tissue. Oleg Zalizniak, Igor Shulov BGU Apoptosis

20. Introduction Functions Apoptotic process Implication in disease References Development Figure: Incomplete differentiation in two toes due to lack of apoptosis Development of an organ or tissue is often preceded by the extensive division and differentiation of a particular cell, with the resultant mass is then “pruned” into the correct form by apoptosis. Apoptosis allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances into the surrounding tissue. Oleg Zalizniak, Igor Shulov BGU Apoptosis

21. Figure: Examples

22. Introduction Functions Apoptotic process Implication in disease References Initiation The process of apoptosis is controlled by a diverse range of cell signals which may originate either extracellularly (extrinsic inducers) or intracellularly (intrinsic inducers). Extracellular signals may include hormones, growth factors, nitric oxide (NO) or cytokines, and therefore must either cross the plasma membrane or transduce to effect a response. Intracellular apoptotic signalling is a response initiated by a cell in response to stress, and may ultimately result in cell suicide. The binding of nuclear receptors by heat, radiation, nutrient deprivation, viral infection and hypoxia are all factors which can lead to the release of intracellular apoptotic signals by a damaged cell. Oleg Zalizniak, Igor Shulov BGU Apoptosis

25. Introduction Functions Apoptotic process Implication in disease References Preparations Figure: Animal cell Before the actual process of cell death is carried out by enzymes, apoptotic signals must be connected to the actual death pathway by way of regulatory proteins. This step allows apoptotic signals to either culminate in cell death, or be aborted should the cell no longer need to die. Oleg Zalizniak, Igor Shulov BGU Apoptosis

26. Introduction Functions Apoptotic process Implication in disease References Preparations Figure: Animal cell Two main methods of achieving regulation are targeting mitochondria functionality, or direct signal (via adapter proteins) to the apoptotic mechanisms. Oleg Zalizniak, Igor Shulov BGU Apoptosis

27. Introduction Functions Apoptotic process Implication in disease References Preparations Figure: Diagram of a human mitochondrion Mitochondria (convert food molecules into energy) are essential to multicellular life, without them a cell ceases to respirate aerobically and quickly dies - a fact exploited by some apoptotic pathways. The whole preparation process requires energy and functioning cell machinery. Oleg Zalizniak, Igor Shulov BGU Apoptosis

28. Introduction Functions Apoptotic process Implication in disease References Preparations Figure: Diagram of a human mitochondrion Mitochondria (convert food molecules into energy) are essential to multicellular life, without them a cell ceases to respirate aerobically and quickly dies - a fact exploited by some apoptotic pathways. The whole preparation process requires energy and functioning cell machinery. Oleg Zalizniak, Igor Shulov BGU Apoptosis

29. Introduction Functions Apoptotic process Implication in disease References Execution Figure: Apoptosis process Cell shrinkage and rounding due to the breakdown of the proteinaceous cytoskeleton by caspases. The cytoplasm appears dense, and the organelles appear tightly packed. The nuclear envelope becomes discontinuous and the DNA inside it is fragmented (karyorrhexis). Nucleus breaks into several discrete bodies due to the degradation of DNA. Oleg Zalizniak, Igor Shulov BGU Apoptosis

30. Introduction Functions Apoptotic process Implication in disease References Execution Figure: Apoptosis vs necrosis cycle The cell membrane shows irregular buds known as blebs. The cell breaks apart into several vesicles called apoptotic bodies, which are then phagocytosed. Oleg Zalizniak, Igor Shulov BGU Apoptosis

31. Introduction Functions Apoptotic process Implication in disease References Removal of dead cells Dying cells that undergo the final stages of apoptosis display phagocytotic molecules on their cell surface. These molecules mark the cell for phagocytosis by cells possessing the appropriate receptors, such as macrophages. Oleg Zalizniak, Igor Shulov BGU Apoptosis

32. Introduction Functions Apoptotic process Implication in disease References Removal of dead cells Figure: A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response. Oleg Zalizniak, Igor Shulov BGU Apoptosis

33. Figure: Normal white blood cell vs apoptotic

34. Figure: Cell undergoing apoptosis

35. Introduction Functions Apoptotic process Implication in disease References Implication in disease Figure: Apoptosis due to injury Defective apoptotic pathways p53 dysregulation - p53 prevents the cell from replicating by stopping the cell cycle at G1 to give the cell time to repair, however it will induce apoptosis if damage is extensive and repair efforts fail. HIV progression (AIDS) - Th lymphocytes depleted. Oleg Zalizniak, Igor Shulov BGU Apoptosis

38. Introduction Functions Apoptotic process Implication in disease References Radiation induced apoptosis Figure: Cell in apoptosis Cancer treatments, radiation and chemotherapeutic agents can destroy tumours by triggering cancer cell apoptosis. On the other hand, cancer cells can develop numerous mechanisms to evade apoptosis through either inactivation of proapoptotic or up-regulation of antiapoptotic factors.[Marsoni, 2004] Oleg Zalizniak, Igor Shulov BGU Apoptosis

39. Introduction Functions Apoptotic process Implication in disease References Radiation induced apoptosis Figure: Cell in apoptosis Moderate irradiation with γ or X-rays or UV light causes apoptosis, and exerts strong anti-inflammatory and immunosuppressive effects. [Reinhard, 2003, Sluyser, 2005] Many tumors display not only an increased proliferation rate, but also an increased rate of apoptosis.[Reinhard, 2003] Oleg Zalizniak, Igor Shulov BGU Apoptosis

40. Introduction Functions Apoptotic process Implication in disease References References I Wikipedia www.wikipedia.org B. Fadeel & S. Orrenius Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. Journal of Internal Medicine 2005; 258: 479–517 S. Marsoni & G. Damia Molecular targeting: new therapeutic strategies to improve tumour apoptosis. Annals of Oncology 15 (Supplement 4); iv229 – iv231, 2004 Oleg Zalizniak, Igor Shulov BGU Apoptosis

41. Introduction Functions Apoptotic process Implication in disease References References II Reinhard E. Voll, Martin Herrmann, Irute Girkontaite, Wasilis Kolowos and Joachim R. Kalden Anti-inflammatory and Immunoregulatory Effects of Apoptotic Cells Apoptosis and Autoimmunity, Wiley-vch 2003, 53-54 Mohammed Al-Rubeai & Martin Fussenegger Cell Engineering Kluwer Academic Publishers, 2004; vol.4 Mels Sluyser Application of Apoptosis to Cancer Treatment Springer, 2005 Oleg Zalizniak, Igor Shulov BGU Apoptosis

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