Test 4. Lecture 35 Flashcards
• Further research has established that
Cdk1 and cyclin B are members of
protein families.
• Different members of these families
control progression through the phases
of the cell cycle.
• Cdk1 controls passage through START
and entry into mitosis in yeasts, in
association with ___________or ________
• In higher eukaryotes, there are multiple
cyclins and multiple Cdk1-related protein
kinases, known as _________ for cyclindependent
kinases.
G1 cyclins or Cln’s.
Cdk’s
The activity of CDk’s is regulated by four mechanisms.
- Association of Cdk’s and cyclin partners.
• Formation of specific Cdk/cyclin complexes is controlled by cyclin
synthesis and degradation. - Activation of Cdk/cyclin complexes requires phosphorylation of threonine at position
160.
This is catalyzed by CAK (Cdk-activating kinase), which is composed of Cdk7/cyclin
H. - Inhibitory phosphorylation of tyrosine near the Cdk amino terminus, catalyzed by
Wee1 protein kinase.
The Cdk’s are then activated by dephosphorylation by Cdc25 protein phosphatases. - Binding of inhibitory proteins CDK INHIBITORS (CKIs)
In mammalian cells, there are two families of Cdk inhibitors: Ink4 and Cip/Kip
The combined effects of these multiple modes of Cdk regulation are responsible
for controlling cell cycle progression in response to checkpoint controls and to
extracellular stimuli.
• PROLIFERATION OF ANIMAL CELLS IS REGULATED BY EXTRACELLULAR GROWTH FACTORS THAT CONTROL PROGRESSION THROUGH THE RESTRICTION POINT IN LATE G1
.
• This implies that intracellular signaling pathways ultimately act to regulate
components of the cell cycle machinery.
General
The D-type cyclins provide one link between growth factor signaling and cell
cycle progression.
- Growth factors stimulate cyclin D1 synthesis through the Ras/Raf/MEK/ERK
pathway. - Cyclin D1 is synthesized as long as growth factors are present.
- Cyclin D1 is also rapidly degraded, so the intracellular concentration falls rapidly
if growth factors are removed.
• As long as growth factors are present through ________,___________complexes
drive cells through the restriction point.
• Defects in cyclin D1 regulation could contribute to the loss of growth regulation
characteristic of cancer cells.
• Many human cancers arise as a result of defects in cell cycle regulation.
G1, Cdk4,6/cyclin D1 complexes
The MCM helicase proteins bind to origins of replication together with ORC (origin recognition complex) proteins in G1 to form a prereplication complex.
• DNA replication is initiated in S phase by Cdk2/cyclin E and the DDK protein kinase. DDK phosphorylates MCM proteins and Cdk2 phosphorylates additional proteins that join the complex and activate MCM.
• Activation of MCM initiates DNA activation and the MCM proteins
move away from the origin with the replication fork.
• The high activity of Cdk’s prevents the MCM proteins from reassociating with
origins during S, G2 and M, so prereplication
complexes can only reform
during G1.
General
Cell cycle arrest at DNA damage checkpoints is mediated by protein kinases
____and _______, that are activated in response to DNA damage.
• They then activate a signaling pathway that leads to cell cycle arrest, DNA
repair, and sometimes, programmed cell death.
- ______ recognizes double-strand breaks; _______ recognizes single-stranded or unreplicated DNA.
- They phosphorylate and activate the _____________s Chk1 and Chk2.
Chk1 and Chk2 phosphorylate and inhibit Cdc25 phosphatases, which are required to activate Cdk1 and Cdk2.
• Inhibition of Cdk2 results in cell `cycle arrest in G1 and S.
• Inhibition of Cdk1 results in
arrest in G2
ATM and ATR
ATM
ATR
checkpoint kinase
In mammalian cells, arrest at the G1 checkpoint is also mediated by protein ________, which is
phosphorylated by both ________and ______—-
• p53 is a transcription factor, and its increased expression leads to
induction of Cdk inhibitor p21
(Cip/Kip family).
• p21 inhibits Cdk2/cyclin E
complexes, leading to cell cycle
arrest in G1
.
p53
ATM and Chk2.
M phase involves a major reorganization of virtually all cell components:
Chromosomes condense, nuclear envelope breaks down, cytoskeleton reorganizes to form the mitotic spindle, and chromosomes move to opposite poles. Cell division (cytokinesis) usually follows.
mitosis is divided into four stages?
- Prophase
- Metaphase
- Anaphase
- Telophase
_________—appearance of condensed chromosomes (two sister chromatids).
The chromatids are attached at the _________, where proteins bind to
form the ________ (site of eventual spindle attachment).
The \_\_\_\_\_\_\_\_\_\_\_ (which duplicated during interphase) separate and move to opposite sides of the nucleus.
They serve as the two poles of the __________, which begins to form
during late prophase.
Prophase
centromere
kinetochore
centrosomes
mitotic spindle
• In higher eukaryotes prophase ends when the nuclear envelope breaks
down (__________).
• In yeasts the__________ remains intact (closed mitosis).
• Spindle pole bodies are embedded in the nuclear envelope; the
nucleus divides after migration of daughter chromosomes
open mitosis
nuclear envelope
_________—transition between prophase and metaphase. Spindle microtubules attach to kinetochores of condensed chromosomes.
Prometaphase
The chromosomes shuffle back and forth until they align on the__________. The cell is then at metaphase.
metaphase plate
Most cells remain only briefly at metaphase before proceeding to
___________
The LINKS BETWEEN SISTER CHROMATIDS BREAK, and they separate and move to
opposite poles of the spindle.
anaphase:
_____________: nuclei re-form and chromosomes decondense. Cytokinesis usually begins during late anaphase and is almost complete by the end of telophase.
Telophase
