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Aging of the inceptive cellular population: the relationship between stem cells and aging.

Symonds CE, Galderisi U, Giordano A - Aging (Albany NY) (2009)

Bottom Line: The average life expectancy worldwide has about doubled and the global population has increased six fold over the past century.The manifestation of this research has been focalized on the causative cellular processes and molecular mechanisms involved.Here we will discuss the efforts of this research in the area of stem cells, delving into the regulatory mechanisms and how their de-regulation could be attributed to aging and age-related diseases.

View Article: PubMed Central - PubMed

Affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, Temple University, Philadelphia, PA 19122, USA.

ABSTRACT
The average life expectancy worldwide has about doubled and the global population has increased six fold over the past century. With improving health care in the developed world there is a proportional augmentation in the treatment necessary for elderly patients occasioning the call for increased research in the area of aging and age-related diseases. The manifestation of this research has been focalized on the causative cellular processes and molecular mechanisms involved. Here we will discuss the efforts of this research in the area of stem cells, delving into the regulatory mechanisms and how their de-regulation could be attributed to aging and age-related diseases.

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Related in: MedlinePlus

Cell cycle in somatic cells vs. ESCs. (a) Cell cycle regulation                                            in somatic cells: mitogen signaling through MAPK pathway activates cyclin D                                            - CDK4/6 kinase activity hypophosphorylating Rb family member proteins.                                            Hypophosphorylated Rb family member proteins bind to E2F transcription                                            factors blocking the transcription of E2F-regulated genes.  To surpass the                                            R point cyclin E - CDK2 kinase activity is activated hyperphosphorylating                                            Rb family member proteins.  Hyperphosphorylated Rb family member proteins                                            are unable to interact with E2F factors, allowing them to activate                                            transcription of genes necessary in the progression of cell cycle. (b)                                            Cell cycle regulation in ESCs as is currently understood.  Mitogen                                            signaling through MAPK pathways seems to be irrelevant in the progression                                            of cell cycle.  There is cell cycle-independent expression of cyclin E -                                            CDK2 maintaining the hyperphosphorylated levels of Rb family member                                            proteins.  This results in cell cycle-independent expression of                                            E2F-regulated genes.  Cyclin B - CDC2 is the only CDK activity that appears                                            to be regulated by the cell cycle.  ESCs have shortened gap phases and an                                            elongated S phase of the cell cycle, with an apparent lack in the R point                                            for G1-S transition.
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Figure 1: Cell cycle in somatic cells vs. ESCs. (a) Cell cycle regulation in somatic cells: mitogen signaling through MAPK pathway activates cyclin D - CDK4/6 kinase activity hypophosphorylating Rb family member proteins. Hypophosphorylated Rb family member proteins bind to E2F transcription factors blocking the transcription of E2F-regulated genes. To surpass the R point cyclin E - CDK2 kinase activity is activated hyperphosphorylating Rb family member proteins. Hyperphosphorylated Rb family member proteins are unable to interact with E2F factors, allowing them to activate transcription of genes necessary in the progression of cell cycle. (b) Cell cycle regulation in ESCs as is currently understood. Mitogen signaling through MAPK pathways seems to be irrelevant in the progression of cell cycle. There is cell cycle-independent expression of cyclin E - CDK2 maintaining the hyperphosphorylated levels of Rb family member proteins. This results in cell cycle-independent expression of E2F-regulated genes. Cyclin B - CDC2 is the only CDK activity that appears to be regulated by the cell cycle. ESCs have shortened gap phases and an elongated S phase of the cell cycle, with an apparent lack in the R point for G1-S transition.

Mentions: Under normal somatic cell cycle conditons, Rb/p105, in the hypophosphorylated state, interacts with E2F transcription factors inhibiting the transcription of genes necessary for the progression of the cell cycle through the restriction point (R point). The phosphorylation levels of Rb/p105 are dependent upon the CDK activity present in the cell. Mitogen signaling through the Ras/Raf/mitogen activated protein kinase (MAPK) pathway activates the cyclin D - CDK4/6 complexes, which are believed to initially activate Rb/p105 activity by hypophosphorylating the unphosphorylated protein. To pass the R point of the cell cycle cyclin E/CDK2 hyperphosphorylates Rb/p105 inhibiting the protein from binding to E2F transcription factors thus initiating the transcription of genes required in the S phase of the cell cycle. To obtain a cell cycle that is less influenced by mitogen variations, stem cells appear to adopt a different regulation mechanism as depicted in Figure 1 [25,26].


Aging of the inceptive cellular population: the relationship between stem cells and aging.

Symonds CE, Galderisi U, Giordano A - Aging (Albany NY) (2009)

Cell cycle in somatic cells vs. ESCs. (a) Cell cycle regulation                                            in somatic cells: mitogen signaling through MAPK pathway activates cyclin D                                            - CDK4/6 kinase activity hypophosphorylating Rb family member proteins.                                            Hypophosphorylated Rb family member proteins bind to E2F transcription                                            factors blocking the transcription of E2F-regulated genes.  To surpass the                                            R point cyclin E - CDK2 kinase activity is activated hyperphosphorylating                                            Rb family member proteins.  Hyperphosphorylated Rb family member proteins                                            are unable to interact with E2F factors, allowing them to activate                                            transcription of genes necessary in the progression of cell cycle. (b)                                            Cell cycle regulation in ESCs as is currently understood.  Mitogen                                            signaling through MAPK pathways seems to be irrelevant in the progression                                            of cell cycle.  There is cell cycle-independent expression of cyclin E -                                            CDK2 maintaining the hyperphosphorylated levels of Rb family member                                            proteins.  This results in cell cycle-independent expression of                                            E2F-regulated genes.  Cyclin B - CDC2 is the only CDK activity that appears                                            to be regulated by the cell cycle.  ESCs have shortened gap phases and an                                            elongated S phase of the cell cycle, with an apparent lack in the R point                                            for G1-S transition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806020&req=5

Figure 1: Cell cycle in somatic cells vs. ESCs. (a) Cell cycle regulation in somatic cells: mitogen signaling through MAPK pathway activates cyclin D - CDK4/6 kinase activity hypophosphorylating Rb family member proteins. Hypophosphorylated Rb family member proteins bind to E2F transcription factors blocking the transcription of E2F-regulated genes. To surpass the R point cyclin E - CDK2 kinase activity is activated hyperphosphorylating Rb family member proteins. Hyperphosphorylated Rb family member proteins are unable to interact with E2F factors, allowing them to activate transcription of genes necessary in the progression of cell cycle. (b) Cell cycle regulation in ESCs as is currently understood. Mitogen signaling through MAPK pathways seems to be irrelevant in the progression of cell cycle. There is cell cycle-independent expression of cyclin E - CDK2 maintaining the hyperphosphorylated levels of Rb family member proteins. This results in cell cycle-independent expression of E2F-regulated genes. Cyclin B - CDC2 is the only CDK activity that appears to be regulated by the cell cycle. ESCs have shortened gap phases and an elongated S phase of the cell cycle, with an apparent lack in the R point for G1-S transition.
Mentions: Under normal somatic cell cycle conditons, Rb/p105, in the hypophosphorylated state, interacts with E2F transcription factors inhibiting the transcription of genes necessary for the progression of the cell cycle through the restriction point (R point). The phosphorylation levels of Rb/p105 are dependent upon the CDK activity present in the cell. Mitogen signaling through the Ras/Raf/mitogen activated protein kinase (MAPK) pathway activates the cyclin D - CDK4/6 complexes, which are believed to initially activate Rb/p105 activity by hypophosphorylating the unphosphorylated protein. To pass the R point of the cell cycle cyclin E/CDK2 hyperphosphorylates Rb/p105 inhibiting the protein from binding to E2F transcription factors thus initiating the transcription of genes required in the S phase of the cell cycle. To obtain a cell cycle that is less influenced by mitogen variations, stem cells appear to adopt a different regulation mechanism as depicted in Figure 1 [25,26].

Bottom Line: The average life expectancy worldwide has about doubled and the global population has increased six fold over the past century.The manifestation of this research has been focalized on the causative cellular processes and molecular mechanisms involved.Here we will discuss the efforts of this research in the area of stem cells, delving into the regulatory mechanisms and how their de-regulation could be attributed to aging and age-related diseases.

View Article: PubMed Central - PubMed

Affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center of Biotechnology, Temple University, Philadelphia, PA 19122, USA.

ABSTRACT
The average life expectancy worldwide has about doubled and the global population has increased six fold over the past century. With improving health care in the developed world there is a proportional augmentation in the treatment necessary for elderly patients occasioning the call for increased research in the area of aging and age-related diseases. The manifestation of this research has been focalized on the causative cellular processes and molecular mechanisms involved. Here we will discuss the efforts of this research in the area of stem cells, delving into the regulatory mechanisms and how their de-regulation could be attributed to aging and age-related diseases.

Show MeSH
Related in: MedlinePlus