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Cell Cycle Regulators: Namrata Sengupta Mds 1 Year Oral Pathology & Microbiology

- The cell cycle consists of interphase (growth phase) and the mitotic phase (division phase). It is tightly regulated by cyclins, cyclin-dependent kinases (Cdks), and other proteins. - Cyclins act as regulatory proteins that activate Cdks at specific phases. Levels of cyclins like D, E, A, and B rise and fall through the cycle. - Key checkpoints ensure DNA replication is complete and chromosomes are properly attached before progression. The tumor suppressor p53 plays a critical role in DNA damage response. - Precise regulation of the cell cycle is vital, as defects can lead to aneuploidy and cancer. The spindle assembly checkpoint in

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Madhura Shekatkar
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134 views33 pages

Cell Cycle Regulators: Namrata Sengupta Mds 1 Year Oral Pathology & Microbiology

- The cell cycle consists of interphase (growth phase) and the mitotic phase (division phase). It is tightly regulated by cyclins, cyclin-dependent kinases (Cdks), and other proteins. - Cyclins act as regulatory proteins that activate Cdks at specific phases. Levels of cyclins like D, E, A, and B rise and fall through the cycle. - Key checkpoints ensure DNA replication is complete and chromosomes are properly attached before progression. The tumor suppressor p53 plays a critical role in DNA damage response. - Precise regulation of the cell cycle is vital, as defects can lead to aneuploidy and cancer. The spindle assembly checkpoint in

Uploaded by

Madhura Shekatkar
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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CELL CYCLE REGULATORS

NAMRATA SENGUPTA
MDS 1ST YEAR
ORAL PATHOLOGY &
MICROBIOLOGY
When a cell has grown to its maximum size it divides & a series of
changes take place to form 2 daughter cells.

It consists of two stages:


1. A non-dividing growing Interphase or I phase
2. A short dividing Mitotic phase or M phase
CELL CYCLE REGULATION
The whole course of cell cycle is tightly regulated by the protein
players:

Cyclin proteins ( Regulatory proteins for cell cycles)


Cyclin dependent kinases (cdk) (catalytic proteins of cell cycle)
Structural maintenance chromosomal proteins
Anaphase promoting complex
NEED OF CELL CYCLE REGULATION
KEY REGULATORS OF CELL CYCLE
• Two types:
1. Cyclin (key regulator protein)
2. Cdk ( cyclin dependent kinases, catalytic protein)
• Besides these two regulators other regulators also have significant
role in cell cycle cycle regulation such as:
1. Rb protein
Tumor suppress protein
2. P protein
53
CYCLINS
 Regulatory proteins of cell cycle & shows
continuous rise and fall during the various stages

 Synthesis begins during G1 phase, increase in


concentration till metaphase, but in anaphase
degraded by the activity of APC
FUNCTIONS OF CYCLIN PROTEINS
Bind to inactive cdk enzymes and cause activation of these
enzymes
Cdc is the active stage of cdk which causes selective
phosphorylation of target proteins in following manner:
-cdc causes transfer of ATP driven phosphate on the serine or
threonine residues of the target protein, hence these cdc are also
called Ser/Thr kinases
-phosphorylation causes covalent modulation of target proteins
Following are the target proteins for cdc in the cell:
E2f
Histones
Nuclear lamins
APC
TYPES OF REGULATORY CYCLINS

1. Cyclin A : G2 cyclin
2. Cyclin B: Mitotic cyclin
3. Cyclin D: G1 cyclin
4. Cyclin E: late G1 S cyclin
D E A B is the working sequence of cyclins
CYCLIN D ( G1 CYCLIN)
Higher concentration reported in G1 phase, hence called G1 cyclin

Binds with cdk2 enzyme & causes the activation of cdk2 by means
of forming cdc2

Helps in progression of cell cycle across G1 phase


CYCLIN E (LATE G1-S CYCLIN)
Concentration begins to increase at the end of G1 phase &
it reaches at the peak during S phase

Binds with cdk4 thus forming active cdc4

Allow the cell to progress from G1 to S phase

Causes activation of replicons in DNA


CYCLIN A ( G2 PHASE)

Peak concentration in G2 phase & allow the cell


cycle progression from G2 to M phase

Activates cdk1 to cdc1


CYCLIN B ( MITOTIC CYCLIN)
Increases at peak during metaphase stage of cell
cycle & it causes the progression of cell from
metaphase to anaphase, activating cdk20 thus
forming cdc20

Cdc20 binds with APC thus APC gets activated


THE CLASSICAL AND MINIMAL MODEL OF CELL CYCLE
CONTROL
CYCLIN DEPENDENT KINASES
 These are ser/thr kinases which act as catalytic
proteins for cell cycle

 Remain inactive when unbound to cyclins

 Thus cyclin is the most important key regulator of


cell cycle
HOW DOES THIS WORK?
Cdks are kinases, enzymes that phosphorylate specific target proteins. The
attached phosphate group acts like a switch, making the target protein more
or less active.

When a cyclin attaches to a cdk, it has two important effects:


- Activates the cdk as a kinase
- Directs it to a specific set of target proteins, ones appropriate to the cell cycle
period controlled by the cyclin
- G1/S Cyclins send cdks to S phase targets ( promoting DNA replication)
- M Cyclins send cdks to M phase targets ( making the nuclear membrane
breakdown)
MATURATION PROMOTING FACTOR (MPF)

• Add phosphate tags to several different proteins in the nuclear


envelope, resulting in its breakdown (a key event in early M phase)
• Activate targets that promote chromosome condensation
• Controls G2 M
ANAPHASE PROMOTING COMPLEX
/CYCLOSOME
• MPF triggers its own destruction by activating the APC/C, a protein
compleX that causes M cyclins to be destroyed starting in anaphase
• Destruction of M cyclin causes cell to move out of mitosis

new daughter cells enter G1


APC/C first adds a ubiquitin tag to a protein called Securin. Securin
inactivates a protein Separase
Securin sent for recycling, Separase gets activated
Separase destroys protein Cohesion that holds sister chromatids
together, allowing them to separate
Spindle assembly checkpoint
• The spindle assembly checkpoint (SAC) is an active signal produced by
improperly attached kinetochores, which is conserved in all eukaryotes.
• The SAC stops the cell cycle by negatively regulating CDC20, thereby
preventing the activation of the polyubiquitylation activities of 
anaphase promoting complex (APC).
• The proteins responsible for the SAC signal compose the 
mitotic checkpoint complex (MCC).
• During the process of cell division, the spindle checkpoint prevents
separation of the duplicated chromosomes until each chromosome is
properly attached to the spindle apparatus. In order to preserve the cell's
identity and proper function, it is necessary to maintain the appropriate
number of chromosomes after each cell division.
• At the metaphase to anaphase transition, this cohesion between sister
chromatids is dissolved, and the separated chromatids are pulled to
opposite sides of the cell by the spindle microtubules.

• The chromatids are further separated by the physical movement of the


spindle poles themselves.

• Premature dissociation of the chromatids can lead to chromosome


missegregation and aneuploidy in the daughter cells.

• Thus, the job of the metaphase checkpoint is to prevent this transition


into anaphase until the chromosomes are properly attached, before the
sister chromatids separate.
The checkpoint ensuring that chromosome segregation is correct
is termed spindle assembly checkpoint (SAC), spindle
checkpoint or mitotic checkpoint. 
Spindle checkpoint defects and cancer
• When the spindle checkpoint misfunctions, this can lead to chromosome
missegregation, aneuploidy and even tumorigenesis

• In fact, aneuploidy is the most common characteristic of human solid tumors


and thus the spindle assembly checkpoint might be regarded as a possible
target for anti-tumour therapy

• Several spindle assembly checkpoint proteins act both as positive and


negative regulators to ensure the proper chromosome segregation in each
cell cycle preventing chromosome instability (CIN) also known as 
genome instability.
-Cdks, cyclins & APC/C are direct regulators of cell cycle transitions.
- Positive regulators like growth factors increase their activity while
negative ones like DNA damage decrease or block activity
- Key to DNA damage response is a protein called p53, a tumor
suppressor often described as the “ guardian of the genome”

- Works on multiple levels to ensure that cells do not pass on their


damaged DNA through cell division:
1. Stops the cell cycle at G1 checkpoint by triggering production of cdk
inhibitor proteins (CKI). It binds to cdk-cyclin compleXes & block their
activity, buying time for DNA repair
2. Activate DNA repair enzymes

3. If DNA damage is not fiXable,


p53 will play its third & final
role: triggering programmed
cell death so damaged DNA is
not passed on.
By ensuring that cells do not divide when their DNA is
damaged, p53 prevents mutations from being passed
on to daughter cells

 When p53 defective or missing: mutation accumulate


quickly, potentially leading to cancer

Out of all the entire human genome, p53 is the single


gene most often mutated in cancers
The Rb/E2F pathway
The tumor suppressor pRb is a well-known transcriptional
repressor of genes involved in S phase progression such as
cyclin E

Proteins of the pRb family eXert this role through association


with transcription factors, primarily with E2F/DP
HETERODIMERS

This association prevents “activating E2Fs “ from promoting


transcriptions
OTHER FACTORS
AUXINS: increase the eXpression of mitotic cyclins

CYTOKININ: necessary for progression through G1S & G2M


transitions
affect the controls that govern the passage of the cell
through cell division cycle

GIBBERELLIC ACID
THANK YOU

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