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CHAPTER 14
Cellular Reproduction
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Overview of the cell cycle
DNA replicationDNA Damage and repair
Nuclear and Cell Division
Regulation of the Cell cycleGrowth Factors and Cell Proliferation
WILL NOT BEIncluded in the exam
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Introduction
• Cells reproduce by the process of cell division.
• Mitosis leads to cells that are genetically identical to their parent.
• Meiosis leads to production of cells with half of the genetic content of the parent.
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14.1 The Cell Cycle (1)
• The cell cycle is the series of stages that a cell goes through. It consists of the M phase and the interphase.
– The M phase includes the process of mitosis and cytokinesis.
– Mitosis last about an hour or so.
– Interphase constitutes the majority of the cell cycle and lasts longer than the M phase (~23 hrs);
– it may extend for days, week, or longer.
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An overview of the eukaryotic cell cycle
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The Eukaryotic Cell Cycle
Cell growth === Cell division=== Cell proliferation
-Duplication of DNA-Replication of DNA-DNA synthesis
---Mitosis/ Cytokinesis---Regulation of Cell cycle
Cell cycleMitosis ~0.5 hrs1-Starts--condension the chromatin2a-sister chromatids2b-nuclear envelop disorganize2c-mitotic spindle3-cytokinesis
G1 8 to 10 hrs
S 6 to 8 hrs
G2 4 to 6 hrs
~23.5 hrs
Go: the cell is out the cell cycle
GoTerminal differentiation
-Protein synthesis ?
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The Cell Cycle (3)
• Cell cycles in vivo
– Three cell types are distinguished based on their capacity to grow and divide.
• Nerve cells have lost the ability to divide, but not all of them.
• Liver cells divides in function of stimulus
• Stem cells will divide frequently.
– Stem cells have asymmetric cell division in which the daughter cells have different fates.
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The Cell Cycle (4)
• Control of the Cell Cycle
– Cell cycle is focused on initiation of DNA replication and initiation of mitosis.
– The cytoplasm contains factors that regulate the state of the nucleus.
• The cytoplasm of a replicating cell contains factors that stimulate initiation of DNA synthesis.
• The cytoplasm of a cell undergoing mitosis contains factors that trigger chromosomal condensation.
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The stages of mitosis in animal and plants cells
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Microtubule Polarity in the Mitotic Spindle
Polarity of MT
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Microtubule Polarity in the Mitotic Spindle
Chromosome alignment and separation
Separated by microtubules, also requires additional proteins like Topoisomerase II, changes in adhesive proteins, (anaphase)and motor proteins (three different roles--mitotic motors-)
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Mitotic Motors
1. Kinetochore microtubulesPlus & minus ends
Depolymerases binds MT and induces depolymerization(chromokinesin, C-terminal and bipolar kinesin)
2. Polar microtubules
ATP hydrolysis is require for MT sliding (C-terminal and bipolar kinesin)
3. Astral microtubules
MT associated (cytoplasmic dynein) with cell cortex at plasma membrane (actin microfilaments)Taxol: it blocks MT
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Cytokinesis and Cell Plate Formation in a Plant Cell
Youtube====50-year cell division puzzle solved
Vesicles from Golgi and ER
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Typical eukaryotic cell cycle --- G1, S, G2, M
---Control / Regulation Systems:
1--Appropriate time and sequence of events2--Each event must be completed3--Respond to external conditions (nutrients and growth factors)
Cell cycle control: Key Transition Points in the Cell Cycle
1
2 3
Chromosome segregation
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Cell Fusion Evidence for the Role of Cytoplasmic Chemical Signals in Cell Cycle Regulation
Specific moleculespresent in the cytoplasmthat induce the transformation
from S to G1(DNA replication genes=proteins)
from M to G1(cell cycle regulation genes=proteins)
Gene: cdc2=cell division cycle--regulate the transition from G2 to M--cdc2: protein kinase
Regulation by phosphorylation?
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Experimental demonstration that cells contain factors that stimulate entry into mitosis
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Cell Cycle Regulation
Mitotic M-cyclinsMitotic M-cdks
S cyclins
G1 cyclinsG1 cdks
http://www-rcf.usc.edu/~forsburg/cclecture.html
How is the cell cycle regulated?
Cdc2 (Cell Division Cycle ) =kinase
Kinase
PhosphataseSubstrate(P1)
Substrate(P2)
(Cyclins)=substrate
(Cyclin-dependent kinase)-CDK-
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Evidence for the Existence of MPF
Maturation promoting factor=MPF=mitotic cdk-cyclin complex
----control the G2 to M transition
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Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
Maximal Enzymatic Activity during the G2-M transition
Substrate: degradation or synthesis?
Regulation: phosphorylation or de-phosphorylation?
CDK Rel
ativ
e ac
tivity
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Phosphorylation and Dephosphorylation in the Activation of a Cdk-Cyclin Complex
Ser= variableThr= 161Tyr=15
MPF-i
mitotic cdk-cyclin complex=MPF
MPF-a
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Fluctuating Levels of Mitotic Cyclin and MPF During the Cell Cycle
Maximal Enzymatic Activity during the G2-M transition
Substrate: degradation or synthesis?
Regulation:?
Rel
ativ
e ac
tivity
CDK
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The Mitotic Cdk Cycle
1-Phosphorylation of lamin in the nuclear lamina induces depolarization
2-Phosphorylation of condensin induces chromosome condensation
3-Phosphorylation of MT induces polymerization
4-Phosphorylation of Anaphase promoting degradation complex.-APC-(ubiquitin ligase)
Cell Cycle Control-I
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The Anaphase-Promoting Complex and the Spindle Checkpoint
Mitotic CDK-cyclin
Anaphase promoting complex(ubiquitin ligase)
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The Anaphase-Promoting Complex and the Spindle Checkpoint
Regulation of the anaphase promoting complex:Binding with cdc20
APC cdc20
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APC cdh1
-degradate mitotic cyclins
SCF controls G1/S through G2/M transitionsUbiquitin ligase-degradation.
SCF
complex
complex
p27 and p21 (cyclin-dependent-kinase inhibitors (CKIs) G1/S cyclin, Cyclin E
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Role of the Rb (Retinoblastoma) Protein in Cell Cycle Control
Cell Cycle Control-II
G1 cdk cyclin
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Cell Cycle Regulation
Mitotic M-cyclinsMitotic M-cdks
S cyclins
G1 cyclinsG1 cdks
How is the cell cycle regulated?
, 6
/A
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DNA Damage: p53-dependent and independent pathways
---DNA damage: ?? can not be repaired--
Cell Cycle Control-III
ATM kinase=ataxia telangiectasia mutated/mutation
ATM=Ionizing radiation
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ATR= UV radiation
ATR kinase: Inactivation of cyclin
DNA Damage: p53-dependent and independent pathways
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http://www.epa.gov
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1. Spindle checkpoint
Kinetochore attachmentMad, Bub, Cdc20
2. DNA replication checkpoint
Completion of DNA synthesisG2/M transitionPhosphorylation of mitotic cyclin
3. DNA damage checkpoint
Cell cycle halted at various stagesp53 – guardian of the genome
Checkpoints=Cell Cycle Control
TimerCdkCyclins
A. DNA integrity (DNA damage)
B. Processes(complete)
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General Model for Cell Cycle Regulation
RegulationNutrients
MitogensEGFPDGF
APC complex
Growth factorsExtra-cellular signals
APC / SCF complex
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Growth Factor Signaling via the Ras Pathway
-bacteria and yeast cell proliferation/division
-mammalian cells cell proliferation/division
Nutrients
Glucose
Growth factor = mitogens
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Growth Factor Signaling via the Ras Pathway
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Growth Factor Signaling via the Ras Pathway
Raf=MAPkkk
MEK=MAPkk
ERK=MAPk
Mitogenic Activated Protein
Serine/Threonine
PM or endosomes
Tyrosine
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The PI3K-Akt Signaling Pathway
Insulin (I) and Insulin-like growth factor (IGF)
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EGF/ PDGF TGF-
(+) (-)
Cell Growth / Proliferation
Mothers Against Decapentaplegic (MAD)Small Mothers Against paralysis (SMA)
Phosphorylation of Smad
Activation of p27, p21 and p15 (Cdk inhibitors)
MAPK
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