生物论文代写:The End Replication Problem Of Cellular Senescence

Aging and Telomeresy

Telomeres are the regulator that regulates the number of cell division. However, normal somatic human cells have a limited capacity to divide, while the tumour cells can divide forever. Studies show that, the telomeric sequences become shorter after each DNA replicates. So, the cells stop dividing (senescent) when the telomere reaches a critically short length. However, when the telomerase introduced into human cells result in maintain a normal chromosome complement.

Oxidative stress:

Senescence provoked by oxidative stress. Several studies shows that, the reactive oxygen species in endothelial cells produced from intracellular or extracellular origin, which can stimulate the growth of senescence by acting at multiply sub-cellular levels. As mentioned above, telomeres are mainly damaged by oxidation. Furthermore, telomerase is inhibited by oxidative damage which lead to effect directly or indirectly in telomeres. However, ROS can stimulate senescence by telomere-independent mechanisms. Finlay, this reaction will damage the DNA and mitochondria. In addition, it may also activate sytosolic response kinases or other redox-sensitive signalling proteins, which are produced in senescence responses.

However, over mutagenic stimulation by acceleration of activated oncogenes has been shown to stimulate senescence. This finding has been observed during the overproduction of Akt, Ras, or Racl activation. However, in this stage the stimulation of senescence is assumed as a result of dysfunction of the cellular redox-balance causing the overproduction of ROS, which may lead to induce p53 activity.

The Role of mitochondria:

Reaction oxygen species (ROS) may destroy the DNA and mitochondria, which may cause dysfunction of mitochondria. However, during normal respiration ROS is generated by mitochondria. Several studies illustrated that; ROS may affect the electron transport chain leading to increase the oxidative burden of the cell. Recently, the significance of mitochondria-derived ROS in the induction of cell senescence has been focused by a study investigating the function of prohibitin-1 (PHB1) in this process. PHB1 is a part of the inner mitochondrial membrane, and assume to be the vital part that maintains the normal mitochondrial function. This can explain that, the function of PHB1 in the cells stimulate mitochondria to generate ROS. Moreover, over production of ROS in mitochondria lead to oxidative destruction of cell components such as proteins, nucleic acids, and lipids.

Senescence and Apoptosis:

The final fate of senescent cells has pathophysiological disorders, due to altered phenotype. Several studies investigated the relation between senescence and apoptosis in endothelial cells. Study by Wagner and his group, shows that, apoptosis is the final fate of senescent cells (Wagner et al., 2001). Whereas, other studies show that, senescent cells don’t undergo apoptosis, but it may induce the sensitivity of these cells to apoptotic stimuli such as TNF-α and oxidized LDL (Hoffmann et al.,2001; Spyridopoulos et al.,2002) . However, this effect may attribute to, p53, p21, and p16 expression on the induction of apoptosis and senescence (Sharpless and DePinho ,2004).. The p53/p21 pathway is involved in apoptosis and senescence (Napolitano et al., 2007), while p16 pathway is only involved in senescence.

Cellular Senescence:

One of the important signals factors that stimulate senescence response is dysfunctional telomeres. However, there are many signals factors that may induce senescence response; such as: strong mitogenic signals, non-telemetric damage DNA, and chromatin perturbations.

Cells arrest growth in association to phenotype are not identifiable as different from replicatively senescent cells, when they provide medium high level of DNA damage, occurs. However, when they deal with agent or expose to mutation, which may damage normal chromatin complex. In addition, strong mitogenic or stress signals can enhance the cell to become senescent. There are many oncogenes that may induce the cell to become senescent such as activation of growth factor signalling like RAS or RAF.

All these persuaders of cellular senescence have a power to cause cancer. As result, chromatin perturbation, DNA damage, and release of oncogenes don’t cause any change in normal cells, but inhence cells to arrest growth in association with a senescent phenotype. This may lead to cellular senescence.

Role of p53 and p16/pRB Tumor-suppressior pathways:

Factors like, activated oncogenes and ionizing radition have been known to transform cells. These agents are involved after cell mutation, which may stimulate the senescence response. However, mutation by senescence leads to dysfunction of the genes encoding contents of the p53 or PRB tumor-suppressor pathways. Both, p53 and PRB are involved in the production of many cellular genes. However, P53 and PRB, each one of them has his pathway to stimulate senescence. The p53 pathways, results to DNA damage, even it may also response to nongenctoxic stress, and temprarly stop cell cycle progression by expression of p21. While p16 and PRB are basically induced by non genetic stress.

The senescent phenotype:

Cellular senescent involve several changes in gene expression. However, a few of which are essential for the growth arrest. Interestingly, senescent cells need two or three features that show senescent phenotypes, such as; irreversible of cell division, and in other cell types, resistance to signals that may lead to apoptotic cell death. It may also affect the cell functions.

However, the induction of senescence phenotype may lead to impediment to normal mitosis creating a mutation in the genetic material such as; genotoxin-induced premature senescence, cumulative DNA damage induced senescence, intrinsic ageing induced senescence (M1), and proliferate history dependent telomere attrition induced mitotic crisis (M2). (Roninoson et al., 2003)

Senescence-Associated B-Galactosidase:

B-Galactosidase is a common feature of senescent cells that is expressed as a natural (pH 6) and called the senescence-associated B-Galactosidase (SA-Bgal). SA-gal expressed in different senescent human cells types, such as: keratinocytes, fibrobalsts, mammary epithelial cells and adult melanocytes. Furthermore, SA-B gal induced by diverse senescence- inducing stimuli such as short telomeres. However, the assay of SA-gal is simple and commonly used as a marker for the senescent phenotype.

生物论文代写:The End Replication Problem Of Cellular Senescence