The Cell-Division Cycle - Chapter 18

interphase, S

• the cell grows continuously during _____, which consists of three phases: G1, S, G2

• DNA replication is confined to __ phase

• G1 is the gap between M phase and S phase

• G2 is the gap between S phase and M phase

nucleus, cytokinesis

• during M phase, the _____ divides in a process called mitosis;

• then, the cytoplasm divides in a process of _______

duplicated

• cell-cycle control is analogous to a controller arm that rotates clockwise, triggering essential processes when it reaches particular transition points on the outer dial

• these processes include DNA replication in S phase and the segregation of ________ chromosomes in mitosis

conserved, cancer

• cell-cycle control is similar in all eukaryotes, and is evolutionarily ________

• failure to regulate cell division can result in _____

cyclin, phosphorylation

A cdk (cyclin-dependent protein kinase) must bind to a regulatory protein called ____ before it can become enzymatically active

• this activation also requires an activating ______ of the Cdk

phosphorylates

once activated, a cyclin-Cdk complex _______ key proteins in the cell that are required to initiate particular steps in the cell cycle

• the cyclin also helps direct the Cdk to the target proteins that the Cdk phosphorylates

entry, M, same

• the formation of active cyclin-Cdk complexes drives various cell-cycle events, including ___ into S phase or M phase

• changes in cyclin concentration and Cdk protein kinase activity are responsible for controlling entry into _ phase

• increasing concentration of the relevant cyclin (M cyclin) helps direct the formation of the active cyclin-Cdk complex (M-Cdk) that drives entry into M phase

• although the enzymatic activity of each type of cyclin-Cdk complex rises and falls during the course of the cell cycle, the concentration of the Cdk component remains the _____

M, meiotic

A xenopus oocyte (nondividing egg) is injected with cytoplasm from a Xenopus egg (dividing cell) in M phase. The cell extract drives the oocyte into __ phase of the first ______ division (a process called maturation), causing the large nucleus to break down and a spindle to form.

maturation promoting factor (MPF)

When the cytoplasm is instead taken from a cleaving egg in interphase, it does not cause the oocyte to enter M phase. Thus, the extract must contain some activity - a _____ ______ _____ - that triggers entry into M phase

different

different Cyclin-Cdk complexes trigger _____ steps in the cell cycle

cyclin degradation

the activity of some Cdks is regulated by _____ ______

destruction, inactive

Ubiquitylation of S or M cyclin by APC/C marks the protein for ______ in proteasomes. The loss of cyclin renders its Cdk partner ___

phosphorylated, Wee1, inactive, Cdc25

Once the M cyclin-Cdk complex is formed, it is _______ at two adjacent sites by an inhibitory protein kinase called ___

• This modification keeps M-Cdk in an ______ state until these (inhibitory) phosphates are removed by an activating protein phosphatase called ____

p27

the inhibitor protein (called ____) binds to an activated cyclin-Cdk complex

• its attachment prevents the Cdk from phosphorylating target proteins required for progress through G1 into S phase

cyclins, G1

G1 phase: to proceed or not to proceed

• Cdks are stably inactivated in G1

• Mitogens promote the production of the ___ that stimulate cell division

• DNA damage can temporarily halt progression through ___

• Cells can delay division for prolonged periods by entering specialized nondividing states

dephosphorylated retinoblastoma (Rb), phosphorylate, S

In the absence of mitogens, ________ ____ protein keeps transcription factors inactive

• mitogens bind cell-surface receptors to activate intracellular signaling pathways, leads to formation and activation of G1-Cdk and G1/S-Cdk complexes

• these complexes _____ Rb, which inactivates the protein —> frees transcription regulators which are required to activate the transcription of genes required for entry into _ phase

p53, p21, inactivates

Specific protein kinases can respond to DNA damage by activating ___ and preventing its rapid degradation

• this activated protein accumulates and stimulations the transcription of Cdk inhibitor protein ___

• The latter binds to G1/S-Cdk and S-Cdk and ______ them —> this causes cell cycle arrest in G1

Cdc6, DNA helicases, pre-replicative complex

During G1, ____ binds to the ORC

• these proteins then load ___ _____ onto DNA to open up the DNA double helix and form the _________ ____

replication origin, DNA polymerase

Once S phase begins, S-Cdk triggers the activation of the ____ ____

• guides the assembly of ___ _______ and associated proteins that initiate DNA synthesis at the replication fork

phosphorylating, inactive, G1

S-Cdk also blocks re-replication by _________ Cdc6 and the ORC

• this keeps these proteins ______ and prevents the reassembly of the pre-replicative complex until Cdks are turned off during the next ___ phase

Cdc25, phosphates, positive

Activated M-Cdk phosphorylates ____ which activates the protein

• the phosphatase activity of this protein can remove inhibitory _____ on the other M-Cdk, creating a ______ feedback loop

compact, mitosis

Condensins help coil each sister chromatid (each DNA double helix) into a more _____ structure that can be more easily segregated during _____

centromere

attachment point for mitotic spindle

central core

condensins are found mainly in the ______ ___ of the chromosome

sister chromatids, protein, mitosis

cohesins join together two adjacent ___ ______ in each duplicated chromosome

• cohesins form large _____ rings that surround sister chromatids to prevent them from coming apart until the rings are broken late in ______

microtubules (of mitotic spindle) and contractile ring (actin and myosin filaments)

two transient cytoskeleton structures mediate M phase in animal cells

separate, divide

in M phase of animal cells, the mitotic spindle first assembles to ______ the duplicated chromosomes

• then, the contractile ring assembles to _____ the cell in two

M (mitosis)

cell division occurs during _ phase of the cell cycle

5, interphase, mitosis

Mitosis is divided into _ stages prior to cytokinesis (cell splitting)

• longest stage: _____

• shortest stage: _____

decondensed, present, increases, replicated, duplicated

during interphase,

• chromosomes in nucleus are ________

• nuclear envelope is _____

• cell _______ in size

• chromosomes are ______ and centrosomes are ______

intact, mitotic spindle, condensing

during Prophase, there is

• _______ nuclear envelope

• forming _____ _____

• ______ duplicated chromosomes with 2 sister chromatids held together along their length

interphase

the centrosome duplicates during _____ to form the mitotic spindles

centrioles, S, G2, opposite, bipolar spindle, chromosomes

• most animal cells contain a single centrosome which consists of a pair of ____ embedded in a protein matrix

• microtubules are seeded by the centrosome protein matrix

• centrosomes duplicate at the start of _ phase and this process is completed by _

• during M phase, the centrosomes begin to nucleate the mitotic asters and separate to _____ ends of the cell

• the microtubules between duplicated centrosomes grow to form the ___ ____

• when the nuclear envelope breaks down exposing _____, spindle microtubules can bind sister chromatids and pull them to opposite ends of the dividing cell

breakdown, spindle microtubules, kinetochores

Prometaphase starts abruptly with the ______ of the nuclear envelope

• chromosomes can now attach to _____ _______ via their _______ and undergo active movement

aligned, equator, sister chromatid

At metaphase, the chromosomes are _____ at the _____ of the spindle, midway between the spindle poles. The kinetochore microtubules on each _____ ______ attach to opposite poles of the spindle

anaphase, kinetochores

sister chromatids separate at the beginning of ___

• the mitotic spindle attaches to the ________ of sister chromatids and pulls them to opposite ends of the cell

bipolar spindle

interpolar microtubules become stabilized to form:

random, plus, phosphorylates

microtubules grow out in _____ directions from duplicated centrosomes

• minus ends anchored in centrosome, plus ends grow out

• ____ ends show dynamic instability, rapidly transitioning between growth and shortening

• M-Cdk ______ microtubule-associated proteins to facilitate this process

astral microtubules

help position centrosomes at opposite poles of cells by interacting with cell cortex, grow out of centrosomes

kinetochore microtubulues

attach directly to kinetochores on sister chromatids at centromere region

interpolar microtubules

overlapping, antiparallel; help position centrosomes to opposite poles of cells

prometaphase, cytoplasm, kinetochores, plus

chromosomes attach to the mitotic spindle at _________

• nuclear envelope breaks down exposing chromosomes to _____

• DNA landmarks (histone modifications) mark regions of the centromere where protein complexes (_____) assemble to facilitate attachment of microtubules

• multiple landmarks exist on mammalian centromeres enabling the attachment of many different microtubules

• microtubules bind to these sites along their sides and in proximity to their ___ ends, which allows the microtubule to continue to grow and shrink while remaining attached

motor proteins, chromosomes

______ _____ and ______ can help assemble bipolar spindle in the absence of centrosomes

duplicated, metaphase plate, dynamic

During metaphase,

• ______ chromosomes line up along the equator, called the _____ ____

• this process requires highly _____ microtubules that continue to grow and shrink

• tug of war process between opposing kinetochores on sister chromatids eventually aligns them

• chromosomes are under tension while they are aligning

• checkpoint!

separate, shorter

at anaphase, the sister chromatids synchronously _____ and are pulled slowly toward the spindle pole to which they are attached

• the kinetochore microtubules get ______ and the spindle poles also move apart, both contributing to chromosome segregation

• cohesins cleaved, ring structure destroyed

Proteolysis, cohesins

_____ triggers sister-chromatid separation at anaphase

• in the transition from metaphase to anaphase, the sister chromatids of duplicated chromosomes suddenly separate, allowing the chromosomes to move toward opposite poles

• to allow this, the _____ linkages that bind sister chromatids together must be degraded

APC/C, securin, separase

_____ (protein) indirectly triggers the separation of sister chromatids by promoting the destruction of cohesins

• it catalyzes the ubiquitylation and destruction of an inhibitory protein called _____, which blocks the activation of a proteolytic enzyme called _____

cohesin

when freed from securin, separase cleaves the ____ complexes, allowing the mitotic spindle to pull the sister chromatids apart

depolymerize

During Anaphase A, sister chromatids are pulled toward opposite poles are kinetochore microtubules _______ (shorten)

• this is the driving force

elongation, sliding, astral, motor proteins

in Anaphase B, the two spindle poles move apart as the result of two separate forces:

1) the _______ and ____ of the interpolar microtubules past one another pushes the two poles apart

2) forces exerted on the outward-pointing ___ microtubules at each spindle pole pull the poles away from each other, toward the cell cortex

• both forces are thought to depend on the action of ___ ____ that associate with both the cell cortex and astral microtubules

nuclear envelope, contractile ring

during telophase, the two sets of chromosomes arrive at the poles of the spindle

• a new _____ _____ reassembles around each set, completing the formation of two nuclei and marking the end of mitosis

• the division of the cytoplasm begins with the assembly of the _____ ____

nuclear pore proteins, lamins, prometaphase, telophase

the phosphorylation of ____ ___ ____ and _____ helps trigger the disassembly of the nuclear envelope at ______

• dephosphorylation of these proteins at _____ helps reverse the process

• vesicles containing nuclear membrane associate with chromosomes and then fuse to re-form nuclear envelope

contractile ring, actin, myosin, decondensing, cleavage furrow

during cytokinesis of an animal cell, the cytoplasm is divided in two by a _____ ___ of ___ and ____ filaments, which pinches the cell into two daughters, each with one nucleus

• reformation of interphase array of microtubules nucleated by the centrosome

• completed nuclear envelope surrounds ____ chromosomes

• contractile ring creating _____ ___

cytokinesis

process by which cell is cleaved into two parts

cytoplasmic cleavage

the mitotic spindle determines the plane of _______ _____

cleavage furrow, identical

the ______ ______ is formed by the action of the contractile ring underneath the plasma membrane (first visible during anaphase)

• transient structure based on actin and myosin filaments

• plane of cleavage and timing of cytokinesis are determined by mitotic spindle, which ensures that the cells are evenly divided and receive ______ sets of chromosomes

Rho-GTPase (RhoA)

mitotic spindle (interpolar microtubules) helps recruit proteins that signal to initiate the assembly of the contractile ring

• the signal activates a ______ in the cell cortex

• the latter controls the assembly and contraction of the contractile ring midway between the spindle poles

anaphase, smaller, disappears

the contractile ring starts to assemble during _____ and is attached to membrane-associated proteins

• the force of contraction is generated by the sliding of actin filaments against myosin filaments (transient structure, as opposed to contractile apparatus in muscle)

• as cytokinesis progresses, this structure gradually becomes _____ and eventually ______ once cells finish dividing

downregulate, integrins, reorganization, rounder

cells _______ their contacts with neighboring cells and to the extracellular matrix

• ______ normally keep cells tightly attached to the extracellular matrix which causes them to be flat

• changes occur from _______ of actin and myosin filaments in the cell cortex

• cells become ______ as they start to divide (ensures even distribution of organelles and other cytosolic components)

• after they finish dividing, cells reform contacts with neighboring cells and the extracellular matrix

apoptosis, eliminated, bone marrow, intestine

programmed cell death, or _____, is a naturally occurring process during embryogenesis

• superfluous sensory neurons are _______

• digits are formed as intervening tissue undergoes this

• in adults, cells in the ____ ______ and the ______ are constantly undergoing this, it balances cell division and keeps organ size constant

quick, orderly

programmed cell death is a ___ and ____ process

true

true/false: apoptotic cells die quickly without damaging neighboring tissues

cytoskeleton, DNA, macrophages, inflammation

in apoptosis

• the _____ collapses and __ breaks up into fragments

• undergoes changes at the cell surface that attracts ______, which quickly engulf the dying cell before it can rupture and spill its contents

• injured or necrotic cells rupture, releasing their cytoplasmic contents into the surrounding tissue, which can cause damaging __________

proteolytic cascade

apoptosis is mediated by an intracellular _____ ____

caspase, procaspase, initiator caspases, protease, inactive dimers ,cleave

in apoptosis,

• an initiator _____ is first made as an inactive monomer called a ______

• an apoptotic signal triggers the assembly of adaptor proteins that bring together and activate a pair of ______ _____, leading to cleavage of a specific site in their ____ domains

• executioner caspases are initially formed as _____ ____, upon cleavage by an initiator caspase, the executioner caspase dimer undergoes an activating conformational change

• the executioner caspases then ____ a variety of key proteins (e.g. lamins), leading to apoptosis

Bax, Bak, outer mitochondrial membrane, cytochrome c, seven, procaspase-9, executioner procaspases

• apoptotic stimuli activate ___ and ___, causing them to aggregate in the _____ _______ ____

• leads to release of ___________ into the cytosol

• the latter then binds to an adaptor protein, causing it to assemble into a ____-armed complex called the apoptosome

• this complex then recruits seven molecules of a specific initiator procaspase (__________). These proteins become activated within the apoptosome and then go on to activate ______ _____ in the cytosol

Fas ligand, Fas, dampen

neighboring cells can produce extracellular signaling factors that can induce cell death

• important for immunity

• Killer T cells (lymphocytes) express a membrane-bound protein (contact-dependent signaling) called ___ _____

• This ligand can recognize the ___ receptor on neighboring cells, triggering apoptosis

• this is a way by which immune cells can ____ immune responses by eliminating unwanted or no longer needed immune cells

• triggers the assembly of specific initiator procaspases that lead to cell death

regulate, survival

animal cells require extracellular signals to survive, grow, and divide

• cells communicate with one another to ______ cell division and _____ using extracellular signaling molecules

• soluble factors secreted by other cells

• membrane-bound proteins

• signals deposited in the extracellular matrix

survival factors, mitogens, growth factors

Positive signals can be divided into three categories:

nerve, trophic, compete

survival factors suppress apoptosis

• during development, excess numbers of ___ cells are generated

• these neurons require survival factors for the continued growth

• survival factors are secreted by their target cells (____ support)

• nerve cells ____ for these limited amounts of survival factors

• nerve cells that win the competition survive, ensuring a 1-1 match and the survival of only neurons that are needed

surface, suppress, Bcl2

survival factors act on ____ receptors and activate intracellular signaling pathways that _____ programmed cell death

• these pathways activate a transcription regulator that stimulates the ____ gene promoter, increasing production of the protein that then acts to block apoptosis

Mitogens, G1, S

_______ stimulate cell division by inhibiting mechanisms that block entry into cell cycle

• these are secreted proteins that bind to cell-surface receptors to activate intracellular signaling pathways

• inhibit block from ___ to ___ phase

PDGF (platelet derived growth factor)

____ is an example of a mitogen

• secreted by platelets at wound site

• causes cells adjacent to wound to divide and heal the wound

after, synthesis, degradation, receptor tyrosine kinase, Tor, protein synthesis, protein degradation

• most cell growth takes place ____ cells have finished dividing

• extracellular growth factors increase the _____ and decrease the ____ of macromolecules

• binding of a growth factor to a ____ ____ ____ (cell-surface receptor) initiates an intracellular signaling pathway that leads to activation of a protein kinase called ___

• The latter acts through multiple targets to stimulate _____ ____ and inhibit ____ ____, leads to net increase in macromolecules and thereby cell growth

Hippo/Taz

animals cells can differ greatly in size

• _________ signaling

• can sense tension/force from environment, pathway activated, tells cells when to stop growing

myostatin, size, number, restrict, positive

some extracellular signal proteins inhibit cell survival, division, or growth

• mutation of the ______ gene leads to a dramatic increase in muscle mass

• both the ____ and ___ of muscle cells is increased

• the phenotype was originally found in cattle and later the gene was identified in mouse, as mutations cause a massive increase in muscle growth

Normally, the gene acts to ___ cell growth by opposing ____ regulators of cell growth

• loss of function mutation —> cell growth NOT controlled