Cell Cycle-Oncogenes-Apoptosis Flashcards
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
- 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.
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.
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.
Metaphase
Chromosomes are aligned across the ___ ____of the cell (equator)
Metaphase
Chromosomes are aligned across the metaphase plate of the cell (equator)
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
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
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
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).
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.
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
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
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.
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.
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.
