cell cycle i molecular cell biology november 6, 2014
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Cell Cycle I Molecular Cell Biology November 6, 2014. Stephen Oh, M.D., Ph.D. Assistant Professor Division of Hematology. Outline. Overview of the cell cycle C ell cycle regulation – fundamental concepts Cancer as a fundamental disruption in cell cycle regulation. - PowerPoint PPT PresentationTRANSCRIPT
Cell Cycle I
Molecular Cell BiologyNovember 6, 2014
Stephen Oh, M.D., Ph.D.Assistant Professor
Division of Hematology
Outline
• Overview of the cell cycle
• Cell cycle regulation – fundamental concepts
• Cancer as a fundamental disruption in cell cycle regulation
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
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?
What critical features are needed for proper guidance through the cell cycle?
Figure 17-13 Molecular Biology of the Cell, 4th Edition
• 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?
The cell cycle is primarily regulated by cyclically activated protein kinases
Figure 17-15, 17-16 Molecular Biology of the Cell, 4th Edition
Malumbres M, Nature Reviews Cancer 2009
Evolution of cell cycle control: from yeast to humans
Table 17-1. Molecular Biology of the Cell, 4th Edition
Overview of major cyclins and Cdks of vertebrates and yeast
Bardin AJ, Nature Rev Mol Cell Biol 2001
Overview of major cyclins and Cdks of vertebrates and yeast
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?
Figure 17-20. Molecular Biology of the Cell, 4th Edition
Cell cycle control depends on cyclical proteolysis
Mechanisms controlling S-phase initiation
Figure 17-30. Molecular Biology of the Cell, 4th Edition
DNA damage leads to cell cycle arrest in G1
Figure 17-33. Molecular Biology of the Cell, 4th Edition
Figure 17-34. Molecular Biology of the Cell, 4th Edition
Overview of the cell cycle control system
Table 17-2. Molecular Biology of the Cell, 4th Edition
Summary of major cell cycle regulatory proteins
Figure 17-41. Molecular Biology of the Cell, 4th Edition
Mitogens stimulate cell division
Figure 17-42. Molecular Biology of the Cell, 4th Edition
Excessive stimulation of mitogenic pathways can lead to cell cycle arrest or cell death
Figure 17-44. Molecular Biology of the Cell, 4th Edition
Extracellular Growth Factors Stimulate Cell Growth
Figure 17-47. Molecular Biology of the Cell, 4th Edition
Extracellular Survival Factors Suppress Apoptosis
Intracellular signaling networks related to cell proliferation and cancer
Hanahan and Weinberg, Cell 2011
Primary myelofibrosis
Essential thrombocythemia
Polycythemia vera
JAK2 V617F
Myeloproliferative neoplasms are clonal disorders derived from hematopoietic stem/progenitor cells
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
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
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
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?
SPADE identifies relevant cell subsets including HSPC
CD34 median expression:
Low High
HSPC
Cell cycle analysis via mass cytometry
Behbehani et al, Cytometry 2012
Cell cycle analysis via mass cytometry
Behbehani et al, Cytometry 2012
Malumbres M, Nature Reviews Cancer 2001
Cell cycle regulators are frequently disrupted in cancer
Malumbres M, Nature Reviews Cancer 2009
Overview of CDK inhibitors in clinical development for cancer therapy
Results thus far have been somewhat disappointing – why?
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
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