Cellular Senescence: A Link between Tumor Suppression and Organismal Aging

< Postmitotic cell vs Mitotic cell > 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) 포유동물의 유기체의 cell type에는 두가지로 구분가능 Pm- 더 이상 세포분화를 할 수 없는 cell (성숙한 뉴론, 골격, 심근, 지방세포) M- 세포분화를 할 수 있는 능력이 있고, 이러한 성질로 인해 tumor로 발전 할 가능성이 높으며 tumorigenic transformation을 누적으로 cancer로 발전할 가능성이 있다. (상피세포, 기질세포)

< In vitro replicative senescence > Introduction < In vitro replicative senescence > 인간과 동물에서 분리된 섬유아세포(fibroblast)는 세포배양에서 계속 자라지 못하고 제한된 횟수만큼 분열한 후 성장이 정지되는데, 이를 생체 외(in vitro) 세포복제 노화(replicative senescence)라 합니다. 생체 외에서 노화한 섬유아세포는 생체 내에서 노화한 섬유아세포와 같은 특성을 보인다고 알려졌으며, 유전자의 발현 양상도 유사한 것으로 보고 되었습니다. 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.

< Hayflick Limit > 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. 정상세포는 제한된 수의 세포 분열을 진행한 후 replicative senescence 또는 세포노화상태에 들어가게 된다. 이러한 현상을 Hayflick limit 라함. 앞선 관찰에서 암시되는 것처럼, 유기체는 구성하는 각 세포가 노화하기 때문에 노화해 간다는 주장이 이 이론입니다. 헤이플리크(Leonard Hayflick)가 제안한 이 모델의 핵심은 모든 세포들이 정해진 횟수만큼 자연적으로 분열하며, 분열이 최대 한도에 도달하면 세포가 노화하여 죽는다는 것입니다. 그러나, 노화의 본질에 대해서는 아무런 설명을 하지 못한다는 것이 이 이론의 단점입니다.

< Cellular senescence > Introduction < Cellular senescence > - Normal human fibroblasts enter a state of irreversible growth arrest after a finite number of cell divisions in vitro caused by telomere shortening but cancer cells appear to bypass this replicative limit and proliferate indefinitely. cellular senescence can also be induced prematurely by a number of cellular stresses such as oncogenic stimuli, oxidative stress, and DNA damage, before reaching their limits of replicative life span. Senescent cells are characterized by a large and flat morphology, senescence-associated acidic β-galactosidase activity, and senescence-associated heterochromatic foci.

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 Replicative(증식) senescence 는 두가지 가설을 지지한다 첫째 celluar(세포의) senescence가 -> 생물체의 aging과 aging phenotype에 기여한다 둘째 세포노화는 암의 development를 억제한다 발표내용은 세포의 노화와 발암과 생물체의 노화의 연결고리를 찾아보고자한다.

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

Suboptimal culture condition Triggers of cellular senescence Cellular senescence Stress Ionizing/ UV irradiation/ ROS/ Nutrient inbalances/ Suboptimal culture condition Chromatin Instability DNA Damage 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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