Apoptosis

Apoptosis Programmed Cell Death

Oleg Zalizniak ([email protected]) Igor Shulov

Department of Nuclear Engineering Ben Gurion University

Radiobiology, 2006/I

Typeset by LATEX

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 Apoptosis

BGU

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 Apoptosis

BGU

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 Apoptosis

BGU

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 Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Introduction 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.

Figure: Cell cycle Oleg Zalizniak, Igor Shulov Apoptosis

Apoptosis plays complementary but opposite role to mitosis in the regulation of animal cell population. BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Introduction 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.

Figure: Cell cycle Oleg Zalizniak, Igor Shulov Apoptosis

Apoptosis plays complementary but opposite role to mitosis in the regulation of animal cell population. BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Introduction 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.

Figure: Cell cycle Oleg Zalizniak, Igor Shulov Apoptosis

Apoptosis plays complementary but opposite role to mitosis in the regulation of animal cell population. BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Apoptosis vs Necrosis

Apoptosis Energy dependent PCD, DNA defragmentation one cell several hours membrane integrity intact no inflammation Dead cells eaten by neighbour cells or macrophages

Oleg Zalizniak, Igor Shulov Apoptosis

Necrosis cell die as result of damage (chemical, thermal, radiation,. . . ) group of cells hours to days membrane integrity faulty acute inflammation Dead cells removed by macrophages (phagocytosis)

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Functions of apoptosis

Cell damage or infection. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis (tumour-suppressing gene p53).

Figure: Cell division: A normal (1 - apoptosis, 2 damaged cell); B - cancer Oleg Zalizniak, Igor Shulov Apoptosis

if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour.

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Functions of apoptosis

Cell damage or infection. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis (tumour-suppressing gene p53).

Figure: Cell division: A normal (1 - apoptosis, 2 damaged cell); B - cancer Oleg Zalizniak, Igor Shulov Apoptosis

if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour.

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Functions of apoptosis

Cell damage or infection. DNA damage from ionizing radiation or toxic chemicals can also induce apoptosis (tumour-suppressing gene p53).

Figure: Cell division: A normal (1 - apoptosis, 2 damaged cell); B - cancer Oleg Zalizniak, Igor Shulov Apoptosis

if a cell is unable to undergo apoptosis, due to mutation or biochemical inhibition, it can continue dividing and develop into a tumour.

BGU

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 Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Development 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.

Figure: Incomplete differentiation in two toes due to lack of apoptosis Oleg Zalizniak, Igor Shulov Apoptosis

Apoptosis allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances into the surrounding tissue. BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Development 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.

Figure: Incomplete differentiation in two toes due to lack of apoptosis Oleg Zalizniak, Igor Shulov Apoptosis

Apoptosis allows the cells to be efficiently phagocytosed and their components reused without releasing potentially harmful intracellular substances into the surrounding tissue. BGU

Figure: Examples

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 Apoptosis

BGU

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 Apoptosis

BGU

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 Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Preparations

Figure: Animal cell

Oleg Zalizniak, Igor Shulov Apoptosis

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.

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Preparations

Two main methods of achieving regulation are targeting mitochondria functionality, or direct signal (via adapter proteins) to the apoptotic mechanisms. Figure: Animal cell

Oleg Zalizniak, Igor Shulov Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Preparations

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.

Figure: Diagram of a human mitochondrion

Oleg Zalizniak, Igor Shulov Apoptosis

The whole preparation process requires energy and functioning cell machinery.

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Preparations

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.

Figure: Diagram of a human mitochondrion

Oleg Zalizniak, Igor Shulov Apoptosis

The whole preparation process requires energy and functioning cell machinery.

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Execution Cell shrinkage and rounding due to the breakdown of the proteinaceous cytoskeleton by caspases. The cytoplasm appears dense, and the organelles appear tightly packed.

Figure: Apoptosis process Oleg Zalizniak, Igor Shulov Apoptosis

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. BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Execution

The cell membrane shows irregular buds known as blebs. The cell breaks apart into several vesicles called apoptotic bodies, which are then phagocytosed. Figure: Apoptosis vs necrosis cycle

Oleg Zalizniak, Igor Shulov Apoptosis

BGU

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 Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Removal of dead cells

Upon recognition, the phagocyte reorganizes its cytoskeleton for engulfment of the cell.

Figure: A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Oleg Zalizniak, Igor Shulov Apoptosis

The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response.

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Figure: Normal white blood cell vs apoptotic

Figure: Cell undergoing apoptosis

Introduction

Functions

Apoptotic process

Implication in disease

References

Implication in disease

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. Figure: Apoptosis due to injury Oleg Zalizniak, Igor Shulov Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Implication in disease

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. Figure: Apoptosis due to injury Oleg Zalizniak, Igor Shulov Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Implication in disease

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. Figure: Apoptosis due to injury Oleg Zalizniak, Igor Shulov Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Radiation induced 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] Figure: Cell in apoptosis Oleg Zalizniak, Igor Shulov Apoptosis

BGU

Introduction

Functions

Apoptotic process

Implication in disease

References

Radiation induced 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] Figure: Cell in apoptosis Oleg Zalizniak, Igor Shulov Apoptosis

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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 Apoptosis

BGU

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 Apoptosis

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