16. Regulation of the cell cycle

Question 1

start point on cell cycle
ubiquitinatina and its role

Answer 1

start (= committment = restriction) point of the cell cycle
A checkpoint in the G1 phase of the mitotic cell cycle where the cell is determined to begin
DNA synthesis. Beyond this point (time point), the cell goes through to S-phase even under
unfavourable conditions (e.g. inhibition of protein synthesis, growth factor withdrawal), and
arrives via S and G2/M to the next G1 phase. If conditions were unfavourable, here it stops and
waits until the circumstances become suitable for a next division.
ubiquitination and its role
Ubiquitin is a small protein. Protein complexes with ubiquitin ligase activity called
ubiquitinating complexes (e.g. APC, SCF) attach chains of ubiquitin covalently to certain target
proteins, thereby labelling them to be recognized and degraded in the proteasomes. Among
others, cyclins involved in the regulation of the cell cycle or misfolded proteins recognised by
the “quality control” in the ER are demolished by this way

Question 2

APC* ubiquitin complem
CDKs

Answer 2

APC (ubiquitinating complex)
Anaphase promoting complex. A regulatory molecular complex which is responsible for the
onset of the anaphase of mitosis. It becomes active after its phosphorylation by MPF and when
the complex binds an additional protein called cdc2. Its targets: securin (a protein which keeps
the separase enzyme in an inactive complex) and the cyclin component of MPF. The
ubiquitinated proteins are degraded in proteasomes.
cyclin dependent kinases (CDK-s)
Cyclin activated kinases which regulate the progression of the cell cycle. Their quantity does
not, but their activity oscillates simultaneously with the concentration of cyclins. Other factors,e.g. activating and inactivating kinases, phosphatases, CDK inhibitor proteins also play a role
in the oscillation of their activity. Different cyclins can bind to a given CDK (but not at the
same time), activating it and also determining its substrate spectrum.

Question 3

ciclins

Answer 3

cyclins (with an example)
Cyclins are involved in the activation of cyclin dependent kinases (CDK) and thereby help to
control the progression of cell cycle from one stage to the next. Cyclins also determine the
substrate spectrum of the CDK molecules. The concentration of cyclins periodically rises and
falls during the cell cycle. Examples: mitotic cyclin (cyclin component of MPF), cyclin D (in
G1), etc.

Question 4

Psotive feedback on the cell cycle regulation
negative feedback on the cell cycle regulation

Answer 4

positive feedback in cell cycle regulation
A direct substrate of MPF involved in the regulation of the cell cycle is a phosphatase which
removes the inhibiting phosphate group from the inactive MPF (containing both an activating
and an inactivating phosphate group), thereby activating the complex. Upon phosphorylation
by MPF, this phosphatase is activated, thus activation of MPF and of the phosphates are
mutually linked, what leads to very rapid MPF activation.
negative feedback in cell cycle regulation
The active MPF (mitosis promoting factor), which is a cyclin-CDK complex, activates among
other substrates the APC (anaphase promoting complex), which ubiquitinates and thereby
degrades the cyclin component of MPF, therefore the cyclin concentration falls down, causing
the MPF to become inactivated, so the cell exits from mitosis.

Question 5

check point control mechanis, 2 example

Answer 5

checkpoint control mechanisms with 2 examples
The checkpoint mechanisms involved in cell cycle regulation halt the cell cycle in case of any
abnormality and give a chance to repair it. Eg., a DNA damage checkpoint operating in G1
inhibits cell cycle progression via the p53 – p21 pathway if DNA double strand breaks are
found. The kinetochore checkpoint does not allow the activation of APC until the appropriate
binding of chromatids to the mitotic spindle has happened.

Question 6

kinetocore checkpoint

Answer 6

kinetochore checkpoint
A checkpoint in the metaphase of cell division, which controls the correct attachment of the
kinetochore microtubules to the chromatids and the balance of forces pulling at the kinetochores
of the two chromatids. In the case of an error, the separation of the chromatids and the
degradation of the mitotic cyclin are prevented, and the cell stops in metaphase, because
activation of the APC is prevented. (MAD2 inhibits cdc20, which therefore cannot activate
APC.)

Question 7

DNA re replication control

Answer 7

DNA re-replication control
A molecule (cdc6) necessary for the start of DNA replication from the replication origins, is
degraded after it has performed its function at the origins, and a new round of replication cannot
start until the synthesis of new cdc6 molecules in the next G1 phase. This mechanism prevents
replication origins from starting replication more than once in a single S phase, thus rereplication of the DNA is not allowed to occur. This allows the faultless passage of genomic
information between consecutive generations.

Question 8

p53, p21

Answer 8

p53 protein
A tumor suppressor gene (antioncogene) product, acting mainly at the G1/S transition. It is a
transcription regulator (transcription factor) of the p21 gene, which is a CDK inhibitor (CDKI).
CELL BIOLOGY – KEY WORDS version: 28 April 2023.
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It is involved in the cell’s response to DNA damage, preventing the cell from entering S phase
until the damage has been repaired, or inducing the cell to commit suicide (apoptosis) if the
damage is too extensive. Mutations inactivating p53 are found in many cancers.
p21 protein
CDK inhibitor protein, it binds to and inhibits the activity of G1-S cyclin-CDK complexes. The
expression of this gene is tightly controlled by the tumor suppressor protein p53. The p21
protein mediates the p53-dependent cell cycle arrest in response to a variety of stress stimuli,
e.g. DNA double strand breaks.

Question 9

myc protein
Origen recognition complex
retinoblastome protein rab

Answer 9

myc gene, Myc protein
The protooncogene myc codes a transcription factor (the Myc protein), which is necessary for
the expression of proteins that allow the cell to progress through G1 to S phase. These include
the first activating G1 cyclin (cyclin D), the component of the SCF complex and the E2F
transcription factor.
origin recognition complex (ORC)
A protein complex binding to the replication origins, which stays bound to the origins during
the whole cell cycle. The ORC together with cdc6 and Mcm helicase makes up the prereplication complex from which DNA replication starts after phosphorylation of ORC by SCDK.
retinoblastoma (Rb) protein
The product of the retinoblastoma tumor suppressor gene. It is a nuclear protein that normally
acts as an inhibitor of the progression of cell cycle in G1 phase, by binding to and keeping the
E2F transcription factor inactive. E2F is involved in the expression of many genes necessary
for the cell cycle progression, which only happens when Rb is phosphorylated by CDKs as a
result of mitotic signaling, and consequently releases E2F.