4-cell_cycle.ppt............................................................

دورة الخلية.............................................................................................................................................................................................................................

1. •ةرودةيلخلا: Cell Cycle
•يهةرتفلايتلارمتاهبةيلخلانيبنيماسقناييولخننايلاتتم
•متيميسقتهذهةرودلاىلإةدعراوطأG1, S, G2 اوفرعيو
مسابُ روَّطلاُ يِنيَبلاخلأاُروطلاُىلاُةفاضلاابريM
•ُروطلاM :نمضتيثودحنيتيلمعماسقنايوون
يمزلابوتيسو.
•ضعبايلاخلايتلاملدعتمسقنتوأتلخدتابسلاتُاهنأبُفصو
يفروطلاGο.

2. •ُةدملُةيلخلاُةرودُرمتست14ُلقتنتُلاوُ،ىنداُدحكُةعاس
لولأاُروطلاُنمُةيلخلاG1 يئايميكلاُتابكرملاُزهجتُىتحُة
وُتاديبيلوُةينيمأُضامحأُنمُماسقنلالُاهجاتحتُيتلاُتايركس
ملاُةيمكُىلعُةيلخلاُماسقناُةعرسوُتقوُدمتعيُكلذلوُداو
مسجلاُاهاقلتيُيتلاُةيئاذغلا.
•يلاخلاُماسقناُىلإُةيلخلاُةرودُعباتتُيفُللخلاُىدؤيُةعرسبُا
ُوأُةيناطرسلاُايلاخلاُدوجوُىلإُىدؤيُاممُمكحتُنودو
ةثيبخلا.

3. •Interphase
•Prophase
•Metaphase
•Anaphase
•Telophase
•Cytokinesis
هيلاتلا لحارملاب رمت نا دبلاف هيلخلا مسقنت يكل
M Phase

4. The Cell Cycle
Phases include:
1.Interphase–Preparation phases for mitosis
2.Mitosis–Cell division or splitting
Interphase
1.G
1(Growth)
2.S
3.G
2 (Growth)

5. The Cell Cycle

6. S-phase
(DNA synthesis
G
1 phase
M
phase
G
2phase
G
0state
Cell division
5 hours
12 hours
15 hours
16 hour cell cycle

7. The cell cycle
ةيولخلا ةرودلا
اندلاُفعاضت
يولخلا ومنلا
تايضعلا فعاضت و
ماسقنلإل ةيلخلا دادعتسإ و يولخلا ومنلا
ماسقنلإا

8. Cell cycle timing
•Yeast 120 minutes (rich medium)
•Insect embryos 15-30 minutes
•Plant and mammals 15-20 hours
•Some adults don’t divide
–Terminally differentiated
–e.g. Nerve cells, eye lens
•Some quiescent unless activated
–Fibroblasts in wound healing

9. Interphase
occurs before mitosis begins
•Chromosomes are copied(# doubles)
•Chromosomes appear as threadlike coils
(chromatin) at the start, but each chromosome and
its copy(sisterchromosome) change to sister
chromatids at end of this phase
CELL MEMBRANE
Nucleus
Cytoplasm

10. ىلولأا ةلصافلا ةرتفلا(G1)
•ةيلخلا ومن ةرتف يهو(Cell growth) اهيف لوازت ثيح
تايضعلا نيوكتك ،اهصصخت لاجم يف اهطاشن ةيلخلا ،
ا ةجسنلأا حلاصإ ،ةريبكلا تائيزجلا ريسكت وأ ءانبو ةفلاتل
تانيتوربلا عيزوتو ،حورجلا ةجيتن.
• لاو ،ةيلخلا فورظ بسحب ةرتفلا هذه رصقت وأ لوطتو
يوونلا ضماحلل ءانب ةرتفلا هذه يف رهظي(DNA). هنأ لاإ
ءانب اهبلطتي يتلا تاميزنلإا طاشن اهتياهن يف دادزي
يوونلا ضماحلا(DNA). لماوع عم تاميزنلإا هذهو
انبلا ةرتف يف لوخدلل ةيلخلا ةئيهت ىلع لمعت ىرخأء.

11. •G1 phase
–Cell checks everything OK for DNA
replication
–Accumulates signals that activate
replication
–Chloroplast and mitochondria
division not linked to cell cycle

12. ءانبلا ةرتف(S phase)
•يوونلا زوبيار يسكويدلا ضماح ةفعاضم اهيف متيو
(DNA)موزومورك لك نم ةخسن لمع متي ثيح ، .
•يف ةلخادلا تانيتوربلا نيوكت ةرتفلا هذه يف متي امك نيوكت
ةاونلا ةيقيقح ايلاخلا يف تاموزوموركلا.
• متت ةدقعم ةيلمع يه تاموزوموركلا ةفعاضم ةيلمعو
يوونلا ضماحلا نم هيجوتب(DNA) ةيلخلا يف دوجوملا
ةفعاضملا لبق

13. •S-phase
–The chromosomes replicate
–Two daughter chromosomes are
called chromatids
–Joined at centromere
–Number of chromosomes in diploid
is four

14. ةيناثلا ةلصافلا ةرتفلا(G2)
•افلا ةرتفلا يف ةيلخلا لخدت ءانبلا ةرتف لامتكا دعب ةلص
تانيتوربلا عيمج ءانب ةرتفلا هذه يف دادزيو ،ةيناثلا عاونأو
يزوبيارلا يوونلا ضماحلا(RNA) ةيلمعل ديهمتك كلذو
ةيلخلا ماسقنا .لا ةئيهت ةرتف ةرتفلا هذه ىلع قلطيوةيلخ

15. •G2-phase
–Cell checks everything is OK for
cell division
–Accumulates proteins that activate
cell division

16. (ةيلخلا ماسقنا ) Mروطلا
•امه نيتيلاتتم نيتيلمعب اهماسقنا ءانثأ ةيلخلا رمت:
•ةيلخلا ةاون ماسقنا
•يمزلابوتيسلا ماسقنلااو(Cytokinesis).
مه تاماسقنلاا نم نيعون ةيلخلا ةاون ماسقنا نمضتيوا:
رشابملا ريغ ماسقنلاا(Mitosis).
يلازتخلاا وأ رشابملا ماسقنلاا(Meiosis).

17. Why have a cell cycle?
•Comprises gaps and distinct phases
of DNA replication and cell division
•If replicating DNA is forced to
condense (as in mitosis) they
fragment
•Similarly if replication before mitosis
–Unequal genetic seperation
•Important to keep DNA replication
and mitosis separate

18. •Important to have divisions in
mitosis
•e.g. Important metaphase complete
before anaphase.
•If not segregation of chromosomes
before attachment of chromatids to
microtubles in opposite poles is
possible
•Down syndrome due to extra
chromosome 21

19. •Gaps provide cell with chance to
assess its status prior to DNA
replication or cell division
•During the cell cycle there are
several checks to monitor status
•These are called checkpoints

21. Checkpoints
•Checkpoint if G1 monitors size of cell
in budding yeast (Saccharomyces
cerevisae)
•At certain size cell becomes
committed to DNA replication
•Called start or replication site

22. Evidence of size checkpoint
•Yeast cells (budding yeast) grown in
rich medium
•Switch to minimal medium
•Cells recently entering G1 (buds)
delayed in G1 (longer to enter S-phase)
•Large cells above threshold size still go
to S-phase at same time as in rich
medium

23. Evidence of size checkpoint
•Yeast in rich medium
–120 minute cell cycle
•Short G1 phase
•Yeast in minimal medium
–Eight hour cell cycle primarily
because of long G1 phase

24. Checkpoints
•Checkpoint 2 in G1 monitors DNA
damage
•Evidence?
–Expose cells to mutagen or irradiation
–Cell cycle arrest in either G1 phase or G2
phase
•The protein p53 involved in cell cycle
arrest
–Tumour suppresser

25. Checkpoints
•Checkpoint in S-phase monitors
completion of DNA replication
–Cell does not enter M-phase until DNA
synthesis is complete
•Checkpoint in G2
–DNA breaks cause arrest
–Otherwise when chromosomes segregate
in mitosis DNA distal to breaak won’t
segregate

26. Checkpoints
•Checkpoint in mitosis
–Senses when mitotic spindles have not
formed
–Arrests in M-phase
–Otherwise unequal segregation of
chromosomes into daughter cells
•Described cell cycle, now I will talk
about genes and proteins that control
this process

27. MPF
•Protein identified that causes mitosis
•Called maturation promoting factor
•MPF in all mitotic cells from yeast to
humans
•Renamed mitosis-promoting factor

28. Mitosis Promoting Factor
Cycles in M-Phase Promoting Factor (MPF) activity
control mitosis. As a protein kinase, MPF likely acts
via phosphorylation of the major histone protein H1
and the major nuclear envelope protein lamin. This
leads to the degradation of the nuclear envelope and
condensation of chromatin into chromosomes in
anticipation of mitosis. Found in all organisms, MPF is
composed of cyclin-dependent kinase (cdk1) and
cyclin B.

29. Properties of MPF
•MPF activity changes through the cell cycle
•MPF activity appears at the G2/M interphase
•and then rapidly decrease

30. How does MPF cause mitosis?
•It’s a protein kinase
–Phosphorylates proteins
•Phosphorylates proteins involved in
mitosis
•Phosphorylates histones causing
chromatin condensation
•Phosphorylates nuclear membrane
proteins (lamins) causing membrane
disruption

31. Characterisation of MPF
•Consists of two subunits; A and B
•Subunit A: Protein kinase
•Subunit B: Regulatory polypeptide
called cyclin B
•Protein kinase present throughout cell
cycle
•Cyclin B gradually increases during
interphase (G1, S, G2)
•Cyclin B falls abruptly in anaphase
(mid-mitosis)

32. Anaphase
Telephase
Interphase
(G1-S-G2)
Prophase
Metaphase
Proteosome
Cyclin B (subunit B)
Protein kinase (subunit A)
MPF}
Ubiquitin

33. How do Cyclin B levels
decrease abruptly
•Proteolytic degradation
•Degraded in a protease complex
present in eukaryotic cells called “The
Proteosome”
•Specific proteins degraded by complex
when tagged by a small peptide called
ubiquitin

34. •Cyclin B is tagged for Proteosome
degradation at anaphase
–Tagged at N-terminus at sequence called
–Destruction box
–DBRP binds to Destruction box
•Guides Ubiquitin ligase to add ubiquitin
molecules to Cyclin B
•Why is Cyclin B only degraded in
anaphase
DBRP = Destruction box recognition protein

35. P
Protein
de-phosphorylase
MPF?
P
DBRP
(active)
Ubiquitin ligase adds ubiquitin
when DBRP binds to the
destruction box
Destruction
box
DBRP
(inactive)

36. •DBRP is normally inactive and is only
activated in anaphase via
phosphorylation
•Possible MPF phosphorylates DBRP
causing Cyclin B destruction
–Binds to the destruction box
–Activates ubiquitin ligase to add ubiquitin to
Cyclin B
–Cyclin B then targeted to the Proteosome
for degradation

37. Cell Cycle Regulation
The cell cycle is regulated by cyclins, cyclin-dependent kinases (CDKs), and cyclin-
dependent kinase inhibitors (CDKIs) and is divided into 4 distinct phases (G1, S, G2, and M).
G0 represents exit from the cell cycle. The cell cycle is driven by CDKs, which are positively
and negatively regulated by cyclins and CDKIs, respectively. The restriction point governs
the transition point beyond which progression through the cell cycle is independent of
external stimuli.
Adapted from Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

38. Regulation of the Cell Cycle
•Cyclin: major control switch for the cell cycle
•Cdk(Cyclin-dependent kinase(phospohorylation)): major control switch;
activated by cyclin; causes G1 S or G2 M.
•Cyclinsform the regulatory subunit and Cdksthe catalytic subunit
•Checkpoints
–DNA damage checkpoints, including tumor suppressor genes
•p53: protein that blocks the cell cycle if DNA is damaged and can
cause apoptosis. A p53 mutation is the most frequent mutation
leading to cancer.
–Spindle checkpoints

39. What Are Cyclin-Dependent Kinases?
Of the many proteins involved in cell cycle control, cyclin-
dependent kinases (CDKs) are among the most important.
CDKs are a family of multifunctional enzymes that can
modify various protein substrates involved in cell cycle
progression.
Specifically, CDKs phosphorylate their substrates by
transferring phosphate groups from ATP to specific
stretches of amino acids in the substrates.
Different types of eukaryotic cells contain different types
and numbers of CDKs. For example, yeast have only a
single CDK, whereas vertebrates have four different ones.

40. •As their name suggests, CDKs require the presence of
cyclinsto become active.
•Cyclins are a family of proteins that have no enzymatic
activity of their own but activate CDKs by binding to them.
•CDKs must also be in a particular phosphorylation state
—with some sites phosphorylated and others
dephosphorylated —in order for activation to occur.
•Correct phosphorylation depends on the action of other
kinases and a second class of enzymes called
phosphatases that are responsible for removing phosphate
groups from proteins.

41. •All eukaryotes have multiple cyclins, each of which acts
during a specific stage of the cell cycle. (In organisms with
multiple CDKs, each CDK is paired with a specific cyclin.)
•All cyclins are named according to the stage at which they
assemble with CDKs.
•Common classes of cyclins include G
1-phase cyclins,
G
1/S-phase cyclins, S-phase cyclins, and M-phase cyclins.
M-phase cyclins form M-CDK complexes and drive the
cell's entry into mitosis; G
1cyclins form G
1-CDK complexes
and guide the cell's progress through the G
1phase; and so
on.
•All CDKs exist in similar amounts throughout the entire
cell cycle. In contrast, cyclin manufacture and breakdown
varies by stage —with cell cycle progression dependent on
the synthesis of new cyclin molecules.

43. CDK CyclinpartnerFunction
Cdk1 CyclinB M phase
Cdk2 CyclinE G1/S transition
Cdk2 CyclinA S phase, G2 phase
Cdk3 CyclinC G1 phase?
Cdk4 CyclinD G1 phase
Cdk5 p35 Transcription
Cdk6 CyclinD G1 phase
Cdk7 CyclinH
CDK-activating
kinase, transcription
Cdk8 CyclinC Transcription
Cdk9 CyclinT Transcription
Known CDKs, their cyclin partners, and their functions in the human

44. Cyclins and CDKs by Cell-Cycle Phase
Phase Cyclin CDK
G0 C Cdk3
G1 D, E
Cdk4, Cdk2,
Cdk6
S A, E Cdk2
G2 A Cdk2, Cdk1
M B Cdk1