Download Cellular Senescence

Cellular Senescence:
A Link between Tumor Suppression
and Organismal Aging
Introduction
< Postmitotic cell vs Mitotic cell >
< Postmitotic cell >
Postmitotic cells have irreversibly lost the ability to proliferate.
(mature neurons, skeletal, cardiac muscl, adipocytes)
< Mitotic cell >
Mitotic cells retain the ability to proliferate.
(epithelial and stromal cells in organs such as the skin, intestine, liver, kidney)
Introduction
< In vitro replicative senescence >
Phase I is the primary culture.
Phase II represents subcultivated cells during the period of exponential replication.
Phase III represents the period when cell replication ceases but metabolism continues.
Cells may remain in this state for at least one year before death occurs.
Introduction
< Hayflick Limit >
- Number of times cells can divide
before they reach replicative senescence.
- The higher the Hayflick limit in the
cells of an organism the longer the
lifespan of that organism.
- Most cancerous cells do not seem to
have a Hayflick limit since they divide
forever.
Introduction
< Cellular senescence >
Replicative senescence..
- Cellular senescence recapitulates aspects
of organismal aging and contributes to aging phenotypes in vivo
- Cellular senescence suppresses the development of cancer
 focuses on the links among
cellular senescence, carcinogenesis, organismal aging
Senescent phenotype
-
senescent cells adopt a characteristic enlarged morphology
and show striking change in gene expression, protein processing, chromatin
organization, metabolism
- senescent cells generally arrest growth with a G1 DNA content.
- decreased rates of protein synthesis and degradation
- many senescent cells are resistant to apoptotic cell death
- an enlarged size (nucleus, lysosomes, vacuoles, mitochondria)
- changes in differentiated cell functions
Senescent phenotype
Examples of characteristics of the senescent phenotype in selected cell types
Triggers of cellular senescence
Chromatin
Instability
Cellular
senescence
DNA
Damage
Stress
Ionizing/
UV irradiation/
ROS/
Nutrient inbalances/
Suboptimal culture
condition
Oncogenes
Short/ dysfunctional
telomeres
Triggers of cellular senescence
< Cell cycle >
Triggers of cellular senescence
p16/Rb pathway
Triggers of cellular senescence
p53/p21 pathway
Triggers of cellular senescence
Telomeres-senescence
- Telomere: protect the DNA ends from degradation and recombination
- Telomere length is maintained
by a specific enzyme called telomerase,
which is not expressed in most normal human somatic cells
- Nature of the DNA replication process and the lack of telomerase,
telomeres become progressively shorter with every round of cell division
- Critical telomere shortening or uncapping of telomere binding proteins
result in telomere dysfunction
and this is thought to initiate DNA damage response signals to activate
p53-dependent checkpoints that contribute to either cellular senescence
or apoptosis.
- Telomere length therefore functions as a mitotic clock
Telomeres-senescence
< Telomeras >
- It is composed of two essential components:
telomerase reverse transcriptase catalytic subunit (hTERT)
and functional telomerase RNA (hTR),
which serves as a template for the addition of telomeric repeats.
- The maintenance of telomeres by telomerase is conserved in most eukaryotes
Telomeres-senescence
< telomere shortening >
- As cells divide, short telomere accumulate
because of the end-replication problem.
- short telomeres
recruit DNA damage proteins
that activate cellular programs of
apoptosis or senescence.
Telomeres-senescence
Schematic drawing of the telomere loss/DNA damage hypothesis of cell aging.
Double (ds) and single strand (ss) DNA break signal can go through either p53
or some other protein independent of p53 (pX) and induce p21.
Cellular senescence and tumor suppression
Cellular senescence and tumor suppression
- Many mammalian cell types senesce
in response to telomere dysfunction, DNA damage,
chromatin perturbations, or supraphysiological mitogenic stimuli.
- p53 and pRB: important tumor suppressor pathways
- Both pathways are crucial for establishing and maintaining
the senescent phenotype
- the senescence response is, very likely,
a failsafe mechanism to prevent the growth of potentially oncogenic cells,
rendering them incapable of tumorigenesis
- a number of reports have shown that
cellular senescence is induced in premalignant tumors,
but is rare in more advanced malignant tumors
Cellular senescence and aging
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