P53

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P53 is a [[Tumour|tumour]] suppressor [[Gene|gene]], which accumulates when [[DNA|DNA]] is damaged beyond repair or the [[Cell|cell]] becomes stressed<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1123</ref>. At the acidic N-terminal, there's a Trans-activation domain (TAD), Proline-rich domain followed by the DNA binding core domain. At the C-terminal are the Tetramerization domain and C-terminal regulatory domain which includes the nuclear localisation signalling domain. In a normal cell where DNA is not damaged or when the cell is not under stress, [[Mdm2|Mdm2]] binds to P53. [[Mdm2|Mdm2]] is a [[Polyubiquitin ligase|polyubiquitin ligase]] which labels P53 for degradation. Mdm2 is not the only E3 Ubiquitin ligase to target p53 for degradation as both Pirh2 and COP1 are also involved<ref>Zhen Wang, Yi Sun,(2010), Targeting p53 for Novel Anticancer Therapy, Transl Oncol, 3(1), 1-12.</ref>. However, when DNA is damaged or the cell is stressed, [[ATM|ATM]] becomes activated which [[Phosphorylation|phosporylates]] P53 preventing the binding of [[Mdm2|Mdm2]]<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105</ref>. Consequently the levels of P53 increase, inducing the production of [[P21|p21]] resulting in the inhibition [[Cdk-Cyclin|Cdk-Cyclin]] complexes which arrest the [[Cell cycle|cell division cycle]]<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105-1107</ref>. When P53 level increases to a high level due to extensive DNA damage, the cell will undergo [[Apoptosis|apoptosis]].  
 
P53 is a [[Tumour|tumour]] suppressor [[Gene|gene]], which accumulates when [[DNA|DNA]] is damaged beyond repair or the [[Cell|cell]] becomes stressed<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1123</ref>. At the acidic N-terminal, there's a Trans-activation domain (TAD), Proline-rich domain followed by the DNA binding core domain. At the C-terminal are the Tetramerization domain and C-terminal regulatory domain which includes the nuclear localisation signalling domain. In a normal cell where DNA is not damaged or when the cell is not under stress, [[Mdm2|Mdm2]] binds to P53. [[Mdm2|Mdm2]] is a [[Polyubiquitin ligase|polyubiquitin ligase]] which labels P53 for degradation. Mdm2 is not the only E3 Ubiquitin ligase to target p53 for degradation as both Pirh2 and COP1 are also involved<ref>Zhen Wang, Yi Sun,(2010), Targeting p53 for Novel Anticancer Therapy, Transl Oncol, 3(1), 1-12.</ref>. However, when DNA is damaged or the cell is stressed, [[ATM|ATM]] becomes activated which [[Phosphorylation|phosporylates]] P53 preventing the binding of [[Mdm2|Mdm2]]<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105</ref>. Consequently the levels of P53 increase, inducing the production of [[P21|p21]] resulting in the inhibition [[Cdk-Cyclin|Cdk-Cyclin]] complexes which arrest the [[Cell cycle|cell division cycle]]<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105-1107</ref>. When P53 level increases to a high level due to extensive DNA damage, the cell will undergo [[Apoptosis|apoptosis]].  
  
Cancer occurs due to the loss of P53 and thus, allows the [[Cell division cycle|cell division cycle]] to progress even though DNA is damaged<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1106</ref>. P53 has also been recognised to be effective in the treatment of cancers, neurodegeneration, ischemia, cholestasis and atherosclerosis; this is proven by the fact that defective P53 gene contributes to the diseases. Treatment involves activating P53 gene for [[Tumour|tumour]] treatment<ref>Amaral JD, Xavier JM, Steer CJ, Rodrigues CM, 2010, Targeting the p53 pathway of apoptosis, Curr Pharm Des, 16(22), 2493-503.</ref>.  
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Cancer occurs due to the loss of p53 gene or when the p53 G1 check-point<ref>Lodish, Berk, Kaiser, et al. (2008) Molecular Cell Biology. Seventh edition. New York. Macmillan Higher Education. Page 1142</ref>&nbsp;does not function properly, thus allowing the [[Cell division cycle|cell division cycle]] to progress even though DNA is damaged<ref>Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1106</ref>, the mutations are passed on to daughter cells, increasing the liklihood of cancerous cells.&nbsp;P53 has also been recognised to be effective in the treatment of cancers, neurodegeneration, ischemia, cholestasis and atherosclerosis; this is proven by the fact that defective P53 gene contributes to the diseases. Treatment involves activating P53 gene for [[Tumour|tumour]] treatment<ref>Amaral JD, Xavier JM, Steer CJ, Rodrigues CM, 2010, Targeting the p53 pathway of apoptosis, Curr Pharm Des, 16(22), 2493-503.</ref>.  
  
There is a number of metals that are highly toxic to p53 activity such as cadmium, aluminium, mercury and lead. Also, the imbalance between copper and zinc concentration, when the first one is in high concentration and the latter one in low, can cause p53 gene becoming unfolded and inactivated. P53 gene is damaged when exposed to environmental factors and toxins such as: herbicides, [[Pesticides|pesticides]], chlorine, [[Fluoride|fluoride]] and radiation. Moreover, the p53 gene can lose its proper functioning as a result of unhealthy dietary habits. Trans fats, [[Acrylamide|acrylamide]] and [[HCAs|HCAs]] found in fried food can play a great role in DNA damage.<sup></sup>
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There is a number of metals that are highly toxic to p53 activity such as cadmium, aluminium, mercury and lead. Also, the imbalance between copper and zinc concentration, when the first one is in high concentration and the latter one in low, can cause p53 gene becoming unfolded and inactivated. P53 gene is damaged when exposed to environmental factors and toxins such as: herbicides, [[Pesticides|pesticides]], chlorine, [[Fluoride|fluoride]] and radiation. Moreover, the p53 gene can lose its proper functioning as a result of unhealthy dietary habits. Trans fats, [[Acrylamide|acrylamide]] and [[HCAs|HCAs]] found in fried food can play a great role in DNA damage.  
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When it is in its activated form, p53 is made up of four identical subunits arranged in a tetramer, if there is a mutation in one of the p53 alleles- such as a missense point mutation, it can often lead to a reduced ability to activate transcription as the subunit will be defective.
  
 
=== References  ===
 
=== References  ===
  
 
<references />
 
<references />

Latest revision as of 22:51, 9 December 2018

P53 is a tumour suppressor gene, which accumulates when DNA is damaged beyond repair or the cell becomes stressed[1]. At the acidic N-terminal, there's a Trans-activation domain (TAD), Proline-rich domain followed by the DNA binding core domain. At the C-terminal are the Tetramerization domain and C-terminal regulatory domain which includes the nuclear localisation signalling domain. In a normal cell where DNA is not damaged or when the cell is not under stress, Mdm2 binds to P53. Mdm2 is a polyubiquitin ligase which labels P53 for degradation. Mdm2 is not the only E3 Ubiquitin ligase to target p53 for degradation as both Pirh2 and COP1 are also involved[2]. However, when DNA is damaged or the cell is stressed, ATM becomes activated which phosporylates P53 preventing the binding of Mdm2[3]. Consequently the levels of P53 increase, inducing the production of p21 resulting in the inhibition Cdk-Cyclin complexes which arrest the cell division cycle[4]. When P53 level increases to a high level due to extensive DNA damage, the cell will undergo apoptosis.

Cancer occurs due to the loss of p53 gene or when the p53 G1 check-point[5] does not function properly, thus allowing the cell division cycle to progress even though DNA is damaged[6], the mutations are passed on to daughter cells, increasing the liklihood of cancerous cells. P53 has also been recognised to be effective in the treatment of cancers, neurodegeneration, ischemia, cholestasis and atherosclerosis; this is proven by the fact that defective P53 gene contributes to the diseases. Treatment involves activating P53 gene for tumour treatment[7].

There is a number of metals that are highly toxic to p53 activity such as cadmium, aluminium, mercury and lead. Also, the imbalance between copper and zinc concentration, when the first one is in high concentration and the latter one in low, can cause p53 gene becoming unfolded and inactivated. P53 gene is damaged when exposed to environmental factors and toxins such as: herbicides, pesticides, chlorine, fluoride and radiation. Moreover, the p53 gene can lose its proper functioning as a result of unhealthy dietary habits. Trans fats, acrylamide and HCAs found in fried food can play a great role in DNA damage.

When it is in its activated form, p53 is made up of four identical subunits arranged in a tetramer, if there is a mutation in one of the p53 alleles- such as a missense point mutation, it can often lead to a reduced ability to activate transcription as the subunit will be defective.

References

  1. Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1123
  2. Zhen Wang, Yi Sun,(2010), Targeting p53 for Novel Anticancer Therapy, Transl Oncol, 3(1), 1-12.
  3. Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105
  4. Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1105-1107
  5. Lodish, Berk, Kaiser, et al. (2008) Molecular Cell Biology. Seventh edition. New York. Macmillan Higher Education. Page 1142
  6. Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, (2008) Molecular Biology of the Cell, 5th edition, New York: Garland Science p.1106
  7. Amaral JD, Xavier JM, Steer CJ, Rodrigues CM, 2010, Targeting the p53 pathway of apoptosis, Curr Pharm Des, 16(22), 2493-503.
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