Cell Cycle I Molecular Cell Biology November 6, 2014
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Cell Cycle I
Molecular Cell BiologyNovember 6, 2014
Stephen Oh, M.D., Ph.D.Assistant Professor
Division of Hematology
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Outline
• Overview of the cell cycle
• Cell cycle regulation – fundamental concepts
• Cancer as a fundamental disruption in cell cycle regulation
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What is the basic function of the cell cycle?
• Accurately duplicate the vast amount of DNA in chromosomes
• Segregate the copies precisely into genetically identical daughter cells
Figure 17-2 Molecular Biology of the Cell, 4th Edition
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The phases of the cell cycle
Figure 17-3. Molecular Biology of the Cell, 4th Edition
• G1 – gap between M and S phases• S – DNA replication• G2 – gap between S and M phases• M - mitosis
• Interphase ~23 hours• M phase ~1 hour
Why are gap phases needed?
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What critical features are needed for proper guidance through the cell cycle?
Figure 17-13 Molecular Biology of the Cell, 4th Edition
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• A clock, or timer, that turns on each event at a specific time
• A mechanism for initiating events in the correct order
• A mechanism to ensure that each event is triggered only once per cycle
• Binary (on/off) switches that trigger events in a complete, irreversible fashion
• Backup mechanisms to ensure that the cycle can work properly even when parts of the system malfunction
• Adaptability so that the system's behavior can be modified to suit specific cell types or environmental conditions
Figure 17-13 Molecular Biology of the Cell, 4th Edition
What critical features are needed for proper guidance through the cell cycle?
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The cell cycle is primarily regulated by cyclically activated protein kinases
Figure 17-15, 17-16 Molecular Biology of the Cell, 4th Edition
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Malumbres M, Nature Reviews Cancer 2009
Evolution of cell cycle control: from yeast to humans
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Table 17-1. Molecular Biology of the Cell, 4th Edition
Overview of major cyclins and Cdks of vertebrates and yeast
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Bardin AJ, Nature Rev Mol Cell Biol 2001
Overview of major cyclins and Cdks of vertebrates and yeast
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Cdk activity is regulated by inhibitory phosphorylation and inhibitory proteins
Figure 17-18, 17-19. Molecular Biology of the Cell, 4th Edition
Why is cell cycle progression governed primarily by inhibitory regulation?
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Figure 17-20. Molecular Biology of the Cell, 4th Edition
Cell cycle control depends on cyclical proteolysis
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Mechanisms controlling S-phase initiation
Figure 17-30. Molecular Biology of the Cell, 4th Edition
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DNA damage leads to cell cycle arrest in G1
Figure 17-33. Molecular Biology of the Cell, 4th Edition
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Figure 17-34. Molecular Biology of the Cell, 4th Edition
Overview of the cell cycle control system
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Table 17-2. Molecular Biology of the Cell, 4th Edition
Summary of major cell cycle regulatory proteins
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Figure 17-41. Molecular Biology of the Cell, 4th Edition
Mitogens stimulate cell division
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Figure 17-42. Molecular Biology of the Cell, 4th Edition
Excessive stimulation of mitogenic pathways can lead to cell cycle arrest or cell death
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Figure 17-44. Molecular Biology of the Cell, 4th Edition
Extracellular Growth Factors Stimulate Cell Growth
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Figure 17-47. Molecular Biology of the Cell, 4th Edition
Extracellular Survival Factors Suppress Apoptosis
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Intracellular signaling networks related to cell proliferation and cancer
Hanahan and Weinberg, Cell 2011
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Primary myelofibrosis
Essential thrombocythemia
Polycythemia vera
JAK2 V617F
Myeloproliferative neoplasms are clonal disorders derived from hematopoietic stem/progenitor cells
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Proliferation/Survival
JAK2JAK2
STAT3/5P P
STAT3/5 STAT3/5P P
P P
STAT3/5
TPOG-CSF
JAK2V617F
STAT3/5 STAT3/5P P
JAK-STAT activation is a hallmark of myeloproliferative neoplasms
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Proliferation/SurvivalTNFαPIM1
JAK2JAK2
STAT3/5P P
STAT3/5 STAT3/5P P
P P
STAT3/5
TPOG-CSF
JAK2V617F
Rux
STAT3/5 STAT3/5P P
PI3K
AKT
S6K
S6
P P
SCFFLT-3L
LNK LNKSOCS
CBL
P PNFkB
Proliferation/SurvivalTNFα, GM-CSFIkBα
IkB degradation
IKKε
IKKγ P
P P
IkBαNFkB
TLRs
TBK1P
IKKα IKKβ
IkBαP
NFkBP P
PIM1BAD
CREB
RAS
RAF
MEK
ERK
Dysregulated signaling networks in myeloproliferative neoplasms
Cell cycle inhibition/Apoptosis
STAT1P
STAT3/5
JAK1JAK1
STAT1 STAT1P P
P P
Ifna
STAT1STAT1P P
STAT1STAT1P P
P
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Spectral limitations of flow cytometry can be overcome with elemental mass cytometry
>30 parameters with single cell
resolution
Labeled cells
Metal conjugatedantibodies
CyTOF2mass cytometer
Mass channel readout
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SPADE links related cell types in a multidimensional continuum of marker expression
Bendall et al Science 2011
How can we visualize data in 30+ dimensions?
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SPADE identifies relevant cell subsets including HSPC
CD34 median expression:
Low High
HSPC
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Cell cycle analysis via mass cytometry
Behbehani et al, Cytometry 2012
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Cell cycle analysis via mass cytometry
Behbehani et al, Cytometry 2012
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Malumbres M, Nature Reviews Cancer 2001
Cell cycle regulators are frequently disrupted in cancer
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Malumbres M, Nature Reviews Cancer 2009
Overview of CDK inhibitors in clinical development for cancer therapy
Results thus far have been somewhat disappointing – why?
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Suggested reading• Alberts et al., Molecular Biology of the Cell, 4th Edition, Garland.
Updated 2001. Chapter 17.– http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.TOC&depth=2
• Malumres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009 Mar;9(3):153-66.– http://www.nature.com/nrc/journal/v9/n3/full/nrc2602.html
• Hanahan and Weinberg. Hallmarks of Cancer: The Next Generation. Cell. 2011 Mar 4;144(5):646-74.– http://www.sciencedirect.com/science/article/pii/S0092867411001279
• Anand S, Huntly BJ. Disordered signaling in myeloproliferative neoplasms. Hematol Oncol Clin North Am. 2012 Oct;26(5):1017-35.– http://www.sciencedirect.com/science/article/pii/S0889858812001281
Contact: [email protected]