Cell Cycle-Oncogenes-Apoptosis Flashcards Preview

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Flashcards in Cell Cycle-Oncogenes-Apoptosis Deck (25):
1

Cell Cycle

  • Cell Division Cycle or Cell Cycle is the fundamental means by which all living things are propagated.
  • An adult human must manufacture many ____ of new cells per ____ simply to maintain status quo.
  • Certain requirements of cell cycle are universal
    •  ______ ___ _____
    • Replicated chromosomes must be ___ ____ into two separate cells
    • A complex set of____  and___ ____ have to be _____ with one another
  • Understanding of cell cycle has undergone revolution in the recent past
    • focus used to be on ____
    • Now the focus is on __ ___ ____ ____ – ie., the ____ that control cell cycle

Cell Cycle

Cell Division Cycle or Cell Cycle is the fundamental means by which all living things are propagated.

An adult human must manufacture many millions of new cells per second simply to maintain status quo.

Certain requirements of cell cycle are universal

 The DNA must faithfully replicate

 Replicated chromosomes must be equally segregated into two separate cells

 A complex set of cytoplasmic and nuclear processes have to be coordinated with one another

Understanding of cell cycle has undergone revolution in the recent past

focus used to be on chromosomes

 now the focus is on cell cycle-control system – ie., the proteins that control cell cycle

2

  • Phases of Cell Cycle
  • The cell cycle of eukaryotes consists of _ phases
    • __ ___ ___ ___
  • Cell cycle typically lasts for about ___ hours in mammalian cells, of which M phase takes only about ____
  • G1, S and G2 constitute _____
    • ____ for ___ ___
    • very___ phase but under the microscope looks deceptively ____
  • G1 Phase
    • AKA first gap phase, is interval between the ___ of ____ and beginning of ___ ____.
    • Late in G1, the cells ___ ___ _____ their _____
  • S Phase
    • ____ _____ as the replication forks advance.
    • ____ of histone and other proteins associated with DNA is _____
    • The amounts of DNA and histones ____ and chromosomes are _____
    • Histones complex with DNA, _____ are formed.
  • G2 Phase
    • Cells prepare to _____ and synthesize ____ for construction of the ______ of the spindle apparatus.
  • M Phase
    • ___ and ___ occurs.
  • After mitosis, some cells _______ G1 phase, other cells ___ the cycle never to divide again, or they enter an ___ G1 phase (sometimes called ___) in which they remain for long periods before they re-enter cell cycle.

Phases of Cell CycleThe cell cycle of eukaryotes consists of 4 phases

G1, S, G2 and M

Cell cycle typically lasts for about 24 hours in mammalian cells, of which M phase takes only about an hour

G1, S and G2 constitute ianterphse

preparation for cell division,

very active phase but under the microscope looks deceptively uneventful!

G1 Phase

AKA first gap phase, is interval between the completion of mitosis and beginning of DNA synthesis.

Late in G1, the cells prepare to duplicate their chromosomes.

S Phase

Nucleosomes disassemble as the replication forks advance.

Synthesis of histone and other proteins associated with DNA is increased.

The amounts of DNA and histones double and chromosomes are duplicated.

Histones complex with DNA, nucleosomes are formed.

G2 Phase

Cells prepare to divide and synthesize tubulin for construction of the microtubules of the spindle apparatus.

M Phase

Mitosis and cytokinesis occurs.

After mitosis, some cells re-enter G1 phase, other cells leave the cycle never to divide again, or they enter an extended G1 phase (sometimes called G0) in which they remain for long periods before they re-enter cell cycle.

 

3

Prophase

The chromosomes begin to ____
The two sister chromatids appear to be ___ at the ___

The two centrosomes (which were duplicated during __-phase) begin to ___ ___ ___ ___ of the ___

The centrosomes begin assembly of the _____-containing structure, the ___ ____with dense ____ forming at each centrosome.

The cytoskeletal microtubules _____ and the ____ is added to the mitotic spindle. 

Prophase

The chromosomes begin to condense.
The two sister chromatids appear to be attached at the centromere.

The two centrosomes (which were duplicated during S-phase) begin to move to opposite ends of the cell.

The centrosomes begin assembly of the microtubule-containing structure, the mitotic spindle with dense asters forming at each centrosome.

The cytoskeletal microtubules disassociate and the tubulin is added to the mitotic spindle. 

4

Prometaphase

The nuclear _____ _______

Centrosomes locate at ____ poles of the cell.

Mitotic spindle microtubules make____ with the _____ to form the ____

Each chromosome develops ____ kinetochores, one for each ___ ____

The kinetochores bind the __ ____ of the mitotic spindle ____ to attach the chromosomes to the mitotic spindle.

The chromosomes are forced toward the ___ of the cell.

Prometaphase

The nuclear membrane breakdown.

Centrosomes locate at opposite poles of the cell.

Mitotic spindle microtubules make contact with the centromere to form the kinetochore.

Each chromosome develops two kinetochores, one for each sister chromatid.

The kinetochores bind the free ends of the mitotic spindle microtubules to attach the chromosomes to the mitotic spindle.

The chromosomes are forced toward the center of the cell.

5

Metaphase

Chromosomes are aligned across the ___ ____of the cell (equator)

Metaphase

Chromosomes are aligned across the metaphase plate of the cell (equator)

6

Anaphase

___ of sister chromatids at centromere, ___ of chromosomes to ____ poles of cell

Anaphase

Separation of sister chromatids at centromere, migration of chromosomes to opposite poles of cell

7

Telophase

Daughter chromosomes ___ the poles.

As telophase concludes, the ___ ____ and ____ re-form, chromatin becomes ____, and the cell again enters___

Telophase

Daughter chromosomes reach the poles.

As telophase concludes, the nuclear envelopes and nucleoli re-form, chromatin becomes diffuse, and the cell again enters interphase

8

Cytokinesis

The ___ divides by a process termed ____, driven by the ____ of a ____ ____ composed of___ and ___ protein subunits.

As the ring of cytoskeletal proteins contracts, a ____ ____is formed _____ to the mitotic spindle and gradually splits the cytoplasm and its contents into two daughter cells

Cytokinesis

The cytoplasm divides by a process termed cleavage, driven by the tightening of a contractile ring composed of actin and myosin protein subunits.

As the ring of cytoskeletal proteins contracts, a cleavage furrow is formed perpendicular to the mitotic spindle and gradually splits the cytoplasm and its contents into two daughter cells

9

Cell Cycle Control

In most cells there are several points in the cell cycle, called ___, at which the cycle can be arrested if previous events have not been completed

___ Major checkpoints are found in the ___ ____ ___ phases of the cell cycle

The G1 checkpoint

  • The ____ Point.
  • The G1 checkpoint ensures that the cell is___ ____ to ___, and that enough ____ are available to support the resulting daughter cells.

The G2 checkpoint

  • Ensures that ___ ____ in __ phase has been completed successfully.

The metaphase checkpoint

  • Ensures that all of the chromosomes are ___ to the ___ ___ by a ____.

The functional consequence of failure to "satisfy" the requirements of a cell-cycle checkpoint is usually ____ by ____ (programmed cell death). 

Cell Cycle Control

In most cells there are several points in the cell cycle, called checkpoints, at which the cycle can be arrested if previous events have not been completed

Three Major checkpoints are found in the G1, G2, and M phases of the cell cycleThe G1 checkpoint

The Restriction Point.

The G1 checkpoint ensures that the cell is large enough to divide, and that enough nutrients are available to support the resulting daughter cells.

The G2 checkpoint

Ensures that DNA replication in S phase has been completed successfully.

The metaphase checkpoint

Ensures that all of the chromosomes are attached to the mitotic spindle by a kinetochore.

The functional consequence of failure to "satisfy" the requirements of a cell-cycle checkpoint is usually death by apoptosis (programmed cell death). 

10

Cell cycle control by cyclins

Cell cycle is controlled by a family of protein kinases known as ____ ___ ____(Cdks).The ___of these kinases ___ and ____ as the cell progresses through the cycle.The oscillations lead directly to ___ changes in the ____ of intracellular proteins that___ or ____ the major events of the cell cycle

  • ___ ____
  • ____
  • _____

Cyclical changes in Cdk activity are controlled by a complex array of enzymes and other proteins.

  • The most important of these Cdk regulators are proteins known as ____

Cdks, unless tightly bound to a ___, they have __ ___ ____ activity.

Complexes formed between cyclins and CDKs cause the cell cycle to ___

Cyclins were originally named as such because they undergo a cycle of ____ and ____ in each cell cycle.

Cdk levels, by contrast, are ____, at least in the simplest cell cycles.

Cyclical changes in cyclin levels result in the cyclic ___ and ___ of the cyclin-Cdk complexes; this activation in turn triggers __ ____ events.

____ cyclins and CDKs control different ____ of cell cycle.

Cell cycle control by cyclinsCell cycle is controlled by a family of protein kinases known as cyclin-dependent kinases (Cdks).The activity of these kinases rises and falls as the cell progresses through the cycle.The oscillations lead directly to cyclical changes in the phosphorylation of intracellular proteins that initiate or regulate the major events of the cell cycle

DNA replication

Mitosis

Cytokinesis

Cyclical changes in Cdk activity are controlled by a complex array of enzymes and other proteins.

The most important of these Cdk regulators are proteins known as cyclins.

Cdks, unless tightly bound to a cyclin, they have no protein kinase activity.

Complexes formed between cyclins and CDKs cause the cell cycle to advance.

Cyclins were originally named as such because they undergo a cycle of synthesis and degradation in each cell cycle.

Cdk levels, by contrast, are constant, at least in the simplest cell cycles.

Cyclical changes in cyclin levels result in the cyclic assembly and activation of the cyclin-Cdk complexes; this activation in turn triggers cell-cycle events.

Different cyclins and CDKs control different stages of cell cycle.

11

Activation of the G1 checkpoint

__ ___ stimulation of ___ cells induces the production of cyclin__

Cyclin D binds to cdk_ and _ (which are always present in cells) and _____ them.

Cyclin D/cdk4/6 complex _____ the _____ gene product (Rb protein).

Phosphorylation of Rb ___ it from the___ ____ _____ (which is normally ____ as it is masked by Rb).

E2F ____ the transcription of genes required for ___ phase.

___ of CyclinD.cdk4/6 complex occurs by __ mechanisms

  • Binding of cyclin-dependent kinase ____ (CDKI=CKI)
  • _____ of cdk
  • ____ _____ _____ 
  • Changes in the ____ of genes encoding ___ ____

Activation of the G1 checkpoint

Growth factor stimulation of quiescent cells induces the production of cyclin D.

Cyclin D binds to cdk4 and 6 (which are always present in cells) and activates them.

Cyclin D/cdk4/6 complex phosphorylates the retinoblastoma gene product (Rb protein).

Phosphorylation Rb releases it from the transcription factor E2F (which is normally inactive as it is masked by Rb).

E2F activates the transcription of genes required for S phase.

Inactivation of CyclinD.cdk4/6 complex occurs by 4 mechanisms

Binding of cyclin-dependent kinase inhibitor (CDKI=CKI)

Phosphorylation of cdk

Ubiquitin-mediated degradation

Changes in the transcription of genes encoding Cdk regulators

12

Checkpoints in tumor cells

In tumor cells, cell cycle checkpoints are often _____ due to genetic defects in the machinery that alternately raises and lowers the _____ of the_______complexes.

These mutations may be:

  • In the genes encoding the ___s or ___s,
  • In genes encoding the proteins that ___ ___ specific cyclin/CDK complexes
  • In genes encoding proteins that____ the ____ of these complexes

In cancers, genes that directly or indirectly regulate the progression of cell cycle are frequently mutated. These can be broadly classified into 2 types:

Tumor suppressor genes

  • Encode proteins that ___ cell cycle

Oncogenes

  • Encode for genes that ___ ____ of cell cycle

Checkpoints in tumor cells

In tumor cells, cell cycle checkpoints are often deregulated due to genetic defects in the machinery that alternately raises and lowers the abundance of the cyclin/CDK complexes.

These mutations may be:

In the genes encoding the cyclins or CDKs,

In genes encoding the proteins that respond to specific cyclin/CDK complexes

In genes encoding proteins that regulate the abundance of these complexes

In cancers, genes that directly or indirectly regulate the progression of cell cycle are frequently mutated. These can be broadly classified into 2 types:Tumor suppressor genes

Encode proteins that inhibit cell cycle

Oncogenes

Encode for genes that promote progression of cell cycle

13

Tumor suppressors and oncogenes

In cancer, dysregulation of tumor suppressors, oncogenes, or ___ are common.

Dysregulation can occur through mechanisms that include ___ ____, changes in ___ ___, or even ____ of the ___ gene.

In the case of tumor suppressors, dysregulation often____ the action of the tumor suppressor (__ of function mutations), thereby contributing to____ ____ through the cell cycle.

In the case of oncogenes, dysregulation often _____ the action of the oncogene (___ of function mutations), thereby favoring ____ through the cell cycle.

Tumor suppressors and oncogenes

In cancer, dysregulation of tumor suppressors, oncogenes, or both are common.

Dysregulation can occur through mechanisms that include point mutations, changes in expression levels, or even deletion of the entire gene.

In the case of tumor suppressors, dysregulation often blocks the action of the tumor suppressor (loss of function mutations), thereby contributing to unchecked progression through the cell cycle.

In the case of oncogenes, dysregulation often upregulates the action of the oncogene (gain of function mutations), thereby favoring progression through the cell cycle.

14

Oncogenes

A gene whose product is involved either in _____ cells in culture or in ____ ____ in animals.

Most oncogenes are mutant forms of normal genes (________) involved in the control of cell ___ or ___.

Conversion, or activation, of a proto-oncogene into an oncogene generally involves a gain-of-function mutation – ___ copy of the mutant allele is sufficient to produce the phenotype – hence ____.

At least three mechanisms can produce oncogenes from the corresponding proto-oncogenes.

  • ___ mutations in a proto-oncogene that result in a ____ acting protein product
  • ___ _____ (gene amplification) of a DNA segment that includes a proto-oncogene, leading to ____ of the encoded protein
  • Gene ____ that brings a growth-regulatory gene under the control of a different ____ and that causes _____ expression of the gene

The proto-oncogenes encode for

____ ____ 
____ for ____

___ ___ ____

___ ___ ____

___ ___

___ ___ ____

 

OncogenesA gene whose product is involved either in transforming cells in culture or in inducing cancer in animals.

Most oncogenes are mutant forms of normal genes (proto-oncogenes) involved in the control of cell growth or division.

Conversion, or activation, of a proto-oncogene into an oncogene generally involves a gain-of-function mutation – one copy of the mutant allele is sufficient to produce the phenotype – hence dominant.

At least three mechanisms can produce oncogenes from the corresponding proto-oncogenes.

Point mutations in a proto-oncogene that result in a constitutively acting protein product

Localized reduplication (gene amplification) of a DNA segment that includes a proto-oncogene, leading to overexpression of the encoded protein

Gene translocation that brings a growth-regulatory gene under the control of a different promoter and that causes inappropriate expression of the gene

The proto-oncogenes encode for

GAGSTC

Growth factors< >Growth factor receptorsSignal transduction proteinsTranscription factorsCell cycle regulatorsRegulators of apoptosis.

15

Oncogenes produced by chromosomal translocation

Two kinds of chromosomal rearrangements have frequently been linked to cancers.

Translocation places the ___sequence of ___gene (Gene B) under the control of ____ sequence for a ____ gene (Gene A).

A classic example of this mechanism is translocation involving chromosomes 8 and 14 in patients with ___ ____

This particular translocation places the ___ proto-oncogene from chromosome 8 under the control of the powerful ____ ___ ___ gene (IGH) promoter on chromosome 14.

This translocation causes ___ levels of MYC overexpression in ____ cells, where the IGH promoter is normally active.

MYC protein normally signals for ___ ____ and when overexpressed, causes ____ proliferation.

Oncogenes produced by chromosomal translocationTwo kinds of chromosomal rearrangements have frequently been linked to cancers.Translocation places the coding sequence of one gene (Gene B) under the control of regulatory sequence for a another gene (Gene A).A classic example of this mechanism is translocation involving chromosomes 8 and 14 in patients with Burkitt's lymphoma.

This particular translocation places the MYC proto-oncogene from chromosome 8 under the control of the powerful immunoglobin heavy chain gene (IGH) promoter on chromosome 14.

This translocation causes high levels of MYC overexpression in lymphoid cells, where the IGH promoter is normally active.

MYC protein normally signals for cell proliferation and when overexpressed, causes enhanced proliferation.

16

Translocation ___ the ___sequences of ___ genes together to generate ___ ____. which are ___ oncogenes.

An example is the ____ chromosome, which is a product of a ____ translocation involving chromosomes 9 and 22.

This translocation fuses the coding sequence of the __ (___ ___ ___) gene on chromosome 22 with the coding sequence of the ___ gene on chromosome 9.

The BCR-ABL fusion protein encoded by the chimeric gene is a protein ___ ___that ____ activates signaling pathways involved in cell ___ and ___

Translocation fuses the coding sequences of two genes together to generate fusion genes, which are potent oncogenes.An example is the Philadelphia chromosome, which is a product of a reciprocal translocation involving chromosomes 9 and 22.

This translocation fuses the coding sequence of the BCR (breakpoint cluster region) gene on chromosome 22 with the coding sequence of the ABL gene on chromosome 9.

The BCR-ABL fusion protein encoded by the chimeric gene is a protein tyrosine kinase that constitutively activates signaling pathways involved in cell growth and proliferation. 

17

Cellular Signaling and Function of Ras

In cells with oncogenic RAS mutation (Example of ___ ____ converting protooncogene to oncogene)

Cells___ the requirement for_____ signaling and the downstream signaling pathways are ____ activated leading to ___ ___ and ___ ___.

Cellular Signaling and Function of RasIn cells with oncogenic RAS mutation (Example of point mutation converting protooncogene to oncogene)

Cells bypass the requirement for upstream signaling and the downstream signaling pathways are constitutively activated leading to uncontrolled proliferation and enhanced survival.

18

Tumor suppressor genes

Tumor-suppressor genes generally encode proteins that in one way or another ____ cell proliferation.

Loss of one or more of these “___” contributes to the development of many cancers.

Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:

  • ___ proteins, such as___ ___ ___, that ___ or ___ progression through a specific stage of the cell cycle
  • ___ for ___ ____ (e.g., tumor-derived growth factor β) that function to___  cell proliferation
  • Checkpoint-control proteins that ____ the cell cycle if DNA is ___ or chromosomes are ____
  • Proteins that promote ____
  • Enzymes that participate in ___ ____

Mutations of tumor suppressor genes are ___of function mutations

____ alleles need to be mutated to produce phenotype – therefore, ____

Loss of tumor suppression occurs due to ___ or ____ mutation of tumor suppressor genes.

Most commonly mutated tumor suppressor gene is ___

Tumor suppressor genes

Tumor-suppressor genes generally encode proteins that in one way or another inhibit cell proliferation.

Loss of one or more of these “brakes” contributes to the development of many cancers.

Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes:

Intracellular proteins, such as cyclin-kinase inhibitor, that regulate or inhibit progression through a specific stage of the cell cycle

Receptors for secreted hormones (e.g., tumor-derived growth factor β) that function to inhibit cell proliferation

Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal

Proteins that promote apoptosis

Enzymes that participate in DNA repair

Mutations of tumor suppressor genes are loss of function mutations

Both alleles need to be mutated to produce phenotype – therefore, recessive.

Loss of tumor suppression occurs due to deletion or inactivating mutation of tumor suppressor genes.

Most commonly mutated tumor suppressor gene is p53.

19

p53 performs multiple functions to maintain cellular homeostasis

p53 protein is a ___ ____ (not an enzyme) which is activated by various signals and regulates several cellular processes such as ___ ___, ___ ___and____

p53 acts as the “___ of the ____” by halting replication in cells that have suffered DNA ___ and targeting unrepaired cells to ___.

Loss of ___ p53 alleles is found in more than ___% of human tumors.

p53 performs multiple functions to maintain cellular homeostasis

p53 protein is a transcription factor (not an enzyme) which is activated by various signals and regulates several cellular processes such as DNA repair, cell cycle and apoptosis.

p53 acts as the “guardian of  the genome” by halting replication in cells that have suffered DNA damage and targeting unrepaired cells to apoptosis.

Loss of both p53 alleles is found in more than 50% of human tumors.

20

Mechanism of cell cycle arrest and DNA repair by p53

In response to DNA-damaging mutagens, ionizing radiation, or UV light, the level of p53 ____.

p53, acting as a transcription factor, stimulates transcription of a ____ that inhibits cyclin-CDK complex and prevents the ____ of ___ and ___ of ___ proteins – ie., causes a ___cell cycle arrest.

The cell is prevented from entering _ phase.

p53 also stimulates the transcription of a number of __ ___ enzymes.

If the DNA repair is successful, p53 induces its own ______ and allows the cells to enter ___ phase

If the DNA repair is not successful, p53 activates several genes in the ____ pathway and causes cell death .

Mechanism of cell cycle arrest and DNA repair by p53

In response to DNA-damaging mutagens, ionizing radiation, or UV light, the level of p53 rises.

p53, acting as a transcription factor, stimulates transcription of a CKI that inhibits cyclin-CDK complex and prevents the phosphorylation of Rb and release of E2F proteins – ie., causes a G1 cell cycle arrest.

The cell is prevented from entering S phase.

p53 also stimulates the transcription of a number of DNA repair enzymes.

If the DNA repair is successful, p53 induces its own downregulation and allows the cells to enter S phase

If the DNA repair is not successful, p53 activates several genes in the apoptotic pathway and causes cell death .

21

Abnormal p53

p53 fails to___ cell division and ___ DNA.

Cell divides without ___ of damaged DNA

Damaged cells continue to divide.

If other damage accumulates the cell can turn ___

Abnormal p53

p53 fails to stop cell division and repair DNA.

Cell divides without repair of damaged DNA

Damaged cells continue to divide.

If other damage accumulates the cell can turn cancerous

22

Apoptosis

The number of cells in a multicellular community is tightly _____ by two mechanisms

  • Rate of cell ___
  • Rate of cell ____

If cells are no longer needed, they ___ ____ by activating an intracellular death program. This process is therefore called programmed cell death or apoptosis (from a Greek word meaning “___ ___,” as leaves from a tree).

Several billions of cells die every ___, even when vast majority of them are ____. Why?

_____- cell die to sculpture structures (digits of a mouse paw)

Cell die when structures are ___ ___ ____

Maintenance of ___ ____

  • Neutrophil engulfs bacteria and then kills itself

Removal of ____ cells

To ___ the number of ___ cells to the number of ___ cells

Cell die in ___

ApoptosisThe number of cells in a multicellular community is tightly regulated by two mechanisms

Rate of cell division

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 or apoptosis (from a Greek word meaning “falling off,” as leaves from a tree).

Several billions of cells die every hour, even when vast majority of them are healthy. Why?

Development - cell die to sculpture structures (digits of a mouse paw)

Cell die when structures are no longer needed

Maintenance of immune system

Neutrophil engulfs bacteria and then kills itself

Removal of injured cells

To match the number of nerve cells to the number of target cells

Cell die in regeneration

23

Overview of apoptosis

Steps:

Chromosomes ___ and cytoplasm ____

Nucleus becomes ____ and DNA is ___ at regular intervals (____)

Cytoplasm becomes _____ and cell extends numerous____

Remnants of the dead cell (____ ____) are ____ by phagocytic cells

Two types of signaling pathways can activate apoptosis

____ pathway

____ pathway

Overview of apoptosisSteps:

Chromosomes condense and cytoplasm shrinks

Nucleus becomes fragmented and DNA is digested at regular intervals (laddering)

Cytoplasm becomes fragmented and cell extends numerous blebs

Remnants of the dead cell (apoptotic bodies) are ingested by phagocytic cells

Two types of signaling pathways can activate apoptosis

Extrinsic pathway

Intrinsic pathway

24

Cell signaling in apoptosis – the extrinsic pathway

Extrinsic apoptotic signaling pathway is activated by the ___ ___ through binding of ___.

Activated death receptor binds ___ molecules of the protein ____ (_ or __).

Procaspases ____ ___ __ ___ to form active caspases.

Caspases 8 and 10 ____ other caspases (_, _ and _).

Caspase 3 cleaves a _____ protein, ___, to a form that activates ____ ____pathway to apoptosis.

Note – Caspases are ___ ____. They are present in cells as _____, zymogen-type enzyme precursors that are activated by ___ ____ of the ____ region of their ____ chain.

Caspases _ and __ are known as ___ caspases

Caspases __ ___ and __ are known as ___ caspases.

Cell signaling in apoptosis – the extrinsic pathway

Extrinsic apoptotic signaling pathway is activated by the death receptors through binding of ligand.

Activated death receptor binds 2 molecules of the protein procaspase (8 or 10).

Procaspases autocatalytically cleave each other to form active caspases.

Caspases 8 and 10 activate other caspases (3, 6 and 7).

Caspase 3 cleaves a Bcl-2 protein, Bid, to a form that activates mitochondrial integrity pathway to apoptosis.

Note – Caspases are cysteine proteases. They are present in cells as procaspases, zymogen-type enzyme precursors that are activated by proteolytic cleavage of the inhibitory region of their polypeptide chain.

Caspases 8 and 10 are known as initiator caspases

Caspases 3, 6 and 7 are known as executor caspases.

25

Cell signaling in apoptosis – the intrinsic pathway

Apoptosis is also induced by ____ signals such as ___ ___, ___ ___ ____,___ ___, release of___ ____.

___ ___ is released from____

Cytochrome c binds to ____ (____ ____ ___ ___) in the cytosol.

Apaf-cytochrome c complex binds to caspase __(____caspase) to form the ____.

The apoptosome activates caspases _,_ and_.

 

 

Cell signaling in apoptosis – the intrinsic pathway

Apoptosis is also induced by intracellular signals such as DNA damage, growth factor withdrawal, cell injury, release of certain steroids.

Cytochrome c is released from mitochondria.

Cytochrome c binds to Apaf (proapoptotic protease activating factor) in the cytosol.

Apaf-cytochrome c complex binds to caspase 9 (initiator caspase) to form the apoptosome.

The apoptosome activates caspases 3, 6 and 7.