Cellular Senescence: A Link between Tumor Suppression and Organismal Aging

1. Cellular Senescence: A Link between Tumor Suppression and Organismal Aging

2. 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)

3. 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.

4. 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.

5. Introduction < Cellular senescence >

6. Replicative senescence.. • Cellular senescence recapitulates aspects • of organismal aging and contributes toaging phenotypes in vivo • Cellular senescence suppresses the development of cancer •  focuses on the links among • cellular senescence, carcinogenesis, organismal aging

7. 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

8. Senescent phenotype Examples of characteristics of the senescent phenotype in selected cell types

9. Chromatin Instability Cellular senescence Triggers of cellular senescence Stress Ionizing/ UV irradiation/ ROS/ Nutrient inbalances/ Suboptimal culture condition DNA Damage Oncogenes Short/ dysfunctional telomeres

10. Triggers of cellular senescence < Cell cycle >

11. Triggers of cellular senescence p16/Rb pathway

12. Triggers of cellular senescence p53/p21 pathway

13. Triggers of cellular senescence

14. 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

15. 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

16. 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.

17. 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.

18. Cellular senescence and tumor suppression

19. 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

20. Cellular senescence and aging

21. Thank You~