Transcript Cell cycle`s deregulation and cardiovascular diseases

Biologia Celular e Molecular II
Cell cycle deregulation and
cardiovascular diseases
Ana Rita Lobo
Diogo Matos
Inês Matos
Biologia Celular e Molecular II
Objectives
• Cell cycle
o Interphase
o Mitosis
• Control System of the Cell Cycle
• Cell cycle machinery and Stroke
Biologia Celular e Molecular II
Cell Cycle
• The cell cycle is the series of events which take
place in the cell and lead to its duplication by
means of replication and duplication of its
previous contents.
Biologia Celular e Molecular II
Cell cycle’s phases
• The cell cycle is generally divided into two
phases:
o Interphase - the cell spends most of its time
performing the functions that make it unique.
o Mitosis - the cell divides into two daughter cells.
Biologia Celular e Molecular II
Interphase
• The interphase stage of the cell cycle includes three
distinctive parts:
o G1 phase- follows mitosis and is the period in which the
cell is synthesizing its structural proteins and enzymes to
perform its functions;
o S phase- the DNA within the nucleus replicates
o G2 phase- the cell prepares for mitosis. Proteins organize
themselves to form a series of fibers called
the spindle, which is essential to chromosome movement
during mitosis
Biologia Celular e Molecular II
Mitotic Phase
• The mitotic phase is the period in the cell
cycle where occurs, the nucleous division.
The mitotic process includes 4 phases:
o
o
o
o
Prophase
Metaphase
Anaphase
Telophase
• After the mitotic phase, the cytokinesis
occurs:
microfilaments contract during
cleavage and assist the division of the cell
into two daughter cells.
Biologia Celular e Molecular II
Control System of the Cell Cycle
• In the majority of
eukaryotic
cells,
the control systems
of the cell cycle
activate
its
progression
in
three points.
Biologia Celular e Molecular II
Control System of the Cell Cycle
Elements involved:
• Cyclins-dependent kinases (CDKs)
• Cyclins
• CDK inhibitor proteins (CKIs)
• Retinoblastoma protein (Rb)
• Cyclical Proteolysis
Biologia Celular e Molecular II
CDKs
• The main components
of the control system of
the cell cycle are a
member of a kinases’
family known as cyclindependent kinases that
can modify various
protein
substrates
involved in cell cycle
progression.
CYCLINS
• Cyclins are a
family of proteins
that have no
enzymatic activity
of their own but
activate CDKs by
binding to them. Cyclin
Cyclin dependt kinase
(CDK)
Biologia Celular e Molecular II
How Do CDKs Control the Cell Cycle?
• All cyclins are named according to the stage at
which they assemble with CDKs. Common
classes of cyclins include G1/S-phase cyclins, Sphase cyclins, and M-phase cyclins.
• Because cyclin-CDK complexes
recognize multiple substrates,
they are able to coordinate
the multiple events that occur
during each phase of the cell
cycle.
Biologia Celular e Molecular II
How Do CDKs Control the Cell Cycle?
Biologia Celular e Molecular II
Inhibitor phosphorilation and CKIs(CDK
inhibitor proteins)
• The rise and fall of the cyclin levels are the
main events that control the activity of CDKs
during the cell cycle.
However, other mechanisms help the activity
of CDKs in specific stages of the cycle.
Biologia Celular e Molecular II
Inhibitor phosphorilation and CKIs(CDK
inhibitor proteins)
• The phosphorilation in a pair of amino acids on
the top of the kinases’ active site inhibits the
cyclin-cdk complex.
• Cells usually use CKIs to help them in the G1-S
regulation activity in the beginning of the cell
cycle. There are some types of CKIs such as
P15,P16,P18 and P19.
Biologia Celular e Molecular II
Retinoblastoma protein (Rb)
• Important target of G1 CDKS
• In mid- to late- G1, Rb is phosphorylate by
cyclin D1- cdk4/6 and cyclin E-cdk2 complexes
• Rb (hyperphosphorylated) is no longer
repressed by E2F
• E2F binds with DP
• Activate genes required for S phase
progression
Biologia Celular e Molecular II
Cell cycle’s deregulation and
cardiovascular diseases
• Hypothesis:
One signal which may control ischemic neuronal death
is the inappropriate activation of cell cycle regulators
including cyclins, cyclin dependent kinases (CDK) and
endogenous cyclin dependent kinases inhibitors (CDKI).
Aberrant activation of these elements triggers neuronal
death
Biologia Celular e Molecular II
Stroke
• Occluded or ruptured of blood vessels and in
some cases cardiac arrest.
Neurons in the affected brain region are
prived of oxigen and glucose.
Ischemic neuronal death is determined by
location, severity and duration of insult.
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
In vitro evidence
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
In vitro evidence
J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cell cycle machinery and stroke, BBA – Molecular Basis of Disease (2006), doi: 10.1016 / j.bbadis.2006.11.009
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
In vitro evidence
• Normal conditions:
• The levels of activity of key cell cycle are
downregulated;
• More activity of CKIs;
• The levels of hypophosphorylated Rb increases
resulting in greater E2F sequestration.
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
In vitro evidence
Ischemic injury conditions:
•
Lose of CKIs
example: CDK inhibitor p27 is reported loss of CKI following oxygen
glucose deprivation (stroke)
•
Increase in Cyclins
example: cyclin D1 protein levels and activation of Cdk2 after
stroke
•
Rb is phosphorylated following hypoxia/reoxygenation
•
Increase in E2F mRNA transcription
Activation of the cell cycle
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
This only showed the activation of cell cycle
components and does not adresss the issue
of whether this signal is required for death
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cell cycle machinery and stroke, BBA – Molecular Basis of Disease (2006), doi: 10.1016 / j.bbadis.2006.11.009
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
• Proceeding 1:use drugs that inactivate the cell
cycle, such as CDK inhibitors like flavopiridol
• Conclusion 1: the cortical neurons have been
protected
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
• Proceeding 2: genetic manipulation
components of the cell cycle
of
• Conclusion 2: in mice with expressing kinase
dead cdk4 or null for its regulator cyclin (D1)
are resistent to hypoxia mediated ischemic
death
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
• Proceeding 3: envision of the cell cycle
pathway with E2F null
• Conclusion 3:cortical neurons derived from
E2F null mice are less susceptible to death by
hypoxia
Furthermore E2F deficiency improves the
recovery of neurons from loss of synaptic
transmission
Biologia Celular e Molecular II
Cell cycle machinery and Stroke
Taken together, these in vitro evidence
strongly implicate the reactivation of cell
cycle components in ischemic neuronal
death.
Biologia Celular e Molecular II
Cell cycle role in atherosclerosis
The atherosclerotic plaque is due to an
overproliferation of endothelial, smooth
muscle, and inflammatory cells and
macrophages
The division of these cells is activated by a
Allograft Inflammatory Factor (AIF-1)
Biologia Celular e Molecular II
Cell cycle role in atherosclerosis
• AIF-1 is not present in normal arteries, and it is
produced by VSMC when they are stimulated.
Constitutive expression of AIF-1 results in a shorter cell
cycle, and aberrant expression of cell cycle proteins.
• AIF-1 actively participates in the upregulation of
VSMC’s proliferation
This happens because AIF-1, alongside with
calmodulin, shortens the G1 and antecipates
the S phase
Biologia Celular e Molecular II
Cell cycle role in atherosclerosis
• This is important to cope with the
inflammatory processes. But if this happens in
ordinary situations, it may cause a
overproduction of VSM cells, obtructing
crucial arteries of the cardiovascular system.
Atherosclerotic Restenosis
Biologia Celular e Molecular II
Bibliography
•
Alberts B., Bray D., Lewis J., M. Raff, Roberts K., & Watson J.D. (1994) Molecular
Biology of the Cell, 3rd Ed. Garland Publishing, Inc. New York.
Netgraphy
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http://www.nature.com/scitable/topicpage/cdk-14046166
http://atvb.ahajournals.org/content/21/9/1421.short
https://sites.google.com/site/kefalikinisi/home/fisiologia-humana-1/celula-e-celulas/ciclo-celular
http://scholar.google.pt/scholar?start=10&q=deregulation+in+cell+cycle+and+cardiovascular+disea
ses&hl=pt-PT&as_sdt=0
Articles
•
J. Rasidian, G.O. Iyirhiaro, D.S. Park, Cell cycle machinery and stroke, BBA –
Molecular Basis of Disease (2006), doi: 10.1016 / j.bbadis.2006.11.009
• Michael V. Autieri, Christopher M. Carbone - Overexpression of Allograft
Inflammatory Factor-1 Promotes Proliferation of Vascular Smooth Muscle Cells by
Cell Cycle Deregulation (Arterioscler Thromb Vasc Biol. 2001;21:1421-1426.)