Team:BrownTwo/Limiter/utility

From 2008.igem.org

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In multicellular organisms, programmed cell death plays a healthy role in development and disease regulation. One might say that the system of apoptosis evolved to provide individual cells a method of succumbing to the greater good of the whole organism.
In multicellular organisms, programmed cell death plays a healthy role in development and disease regulation. One might say that the system of apoptosis evolved to provide individual cells a method of succumbing to the greater good of the whole organism.
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As can be observed in the figure below, the genetic underpinnings that encode for apoptosis are truly immense.  
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As can be observed in the figure below, the genetic underpinnings that encode for apoptosis are truly immense, and are intricately linked to those for cell proliferation.  
[[Image:Signal_transduction_pathways.png|center|thumb|700px]]
[[Image:Signal_transduction_pathways.png|center|thumb|700px]]
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Given the function of apoptosis in defining cell fate, it should come as no surprise that multiple disease states are characterized by an inactive or reduced apoptotic response. When apoptosis cannot proceed, often due to mutations in the genes responsible for initiating the pathway, cell proliferation can occur unchecked.  This allows for propagation of mutated DNA as well as an abnormal accumulation of cells.  This phenotype is highly characteristic of tumor formation in multicellular organisms.   
Given the function of apoptosis in defining cell fate, it should come as no surprise that multiple disease states are characterized by an inactive or reduced apoptotic response. When apoptosis cannot proceed, often due to mutations in the genes responsible for initiating the pathway, cell proliferation can occur unchecked.  This allows for propagation of mutated DNA as well as an abnormal accumulation of cells.  This phenotype is highly characteristic of tumor formation in multicellular organisms.   
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In designing a system , one might desire
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In designing a system to target abnormally-absent apoptosis, one can consider two approaches.  One could identify a key anti-apoptotic factor that requires down-regulation or, conversely, target a pro-apoptotic factor that requires up-regulation.  For the former, one might consider X-linked Inhibitor of Apoptosis (XIAP), which, while not present on the above figure, is responsible for inhibiting caspases (Vucic and Fairbrother, 2007).  Caspase activation in the apoptotic pathway can be considered to be a point of no return, a trigger for the irreversible decision to undergo cellular suicide.  Downregulation of XIAP should thus enable commencement of apoptosis.  Alternatively, mutations in the gene encoding p53 have been cited to exist in  (Toledo and Wahl, 2006).
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Carcinogenesis  is characterized by the
 
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Through an intricate balance between oncogenes, which are described for their ability to result in a cancer phenotype when overexpressed
 
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With respect to its role in the cancer phenotype, two theories dominate the discussion about the relationship between
 
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=Apoptosis in yeast=
=Apoptosis in yeast=
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While still an ongoing debate, there are increasingly more signs that yeast undergo.  Despite the fact that there seems, that yeast undergo a similar programmed cell death  
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While still an ongoing debate, there is increasingly more evidence that yeast undergo programmed cell death.  Despite the fact that there seems, that yeast undergo a similar programmed cell death  
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*medical
 
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*medical
=Research=
=Research=
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 +
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Carcinogenesis  is characterized by the
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 +
Through an intricate balance between oncogenes, which are described for their ability to result in a cancer phenotype when overexpressed
 +
 +
 +
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With respect to its role in the cancer phenotype, two theories dominate the discussion about the relationship between
=References=
=References=
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*directed evolution (includes epigenetics?)
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1. Toledo and Wahl, Regulating the p53 pathway:in vitro hypotheses, in vivo veritas, Nature Reviews vol 6. 2006
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2. Vucic and Fairbrother, The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer, Clin Cancer Res. 2007;13(20)

Revision as of 02:51, 30 October 2008



Contents

The utility of threshold limitation

Much as excessive signal levels can destroy a radio transmitter, excessive genetic expression can cause damage in living systems. While cells are usually well-equipped to modulate their own transcriptional behavior, an investigation into pathological gene expression indicates that many situations arise wherein the expected regulatory response fails. Our device is designed to augment endogenous gene regulatory pathways.

While one can surely identify numerous cases of abnormal gene expression in cellular systems, we turn our attention to one particular network related to a crucial decision in cell fate, apoptosis.


Cellular suicide and the cancer phenotype

In response to either stressful circumstances or communication from neighbors, cells will often undergo a highly regulated process that results in cell death, known as apoptosis. Pro-apoptotic and anti-apoptotic factors expressed in a viable cell strike an ongoing balance that codes for cell survival. Such a balance tilts in favor of an apoptotic cell fate in the presence of appropriate stimuli, like oxidative stress or UV treatment.

In multicellular organisms, programmed cell death plays a healthy role in development and disease regulation. One might say that the system of apoptosis evolved to provide individual cells a method of succumbing to the greater good of the whole organism.

As can be observed in the figure below, the genetic underpinnings that encode for apoptosis are truly immense, and are intricately linked to those for cell proliferation.

Signal transduction pathways.png

An apoptotic response generally entails changes to multiple nodes in this robust network of genes. One important point to note is that apoptosis can be triggered extrinsically, from factors in the cell's environment, or intrinsically, when the cell recognizes that it should not continue to proliferate. Due to its complexity, the system is still being explored, especially for its potential involvement in cancer.

Given the function of apoptosis in defining cell fate, it should come as no surprise that multiple disease states are characterized by an inactive or reduced apoptotic response. When apoptosis cannot proceed, often due to mutations in the genes responsible for initiating the pathway, cell proliferation can occur unchecked. This allows for propagation of mutated DNA as well as an abnormal accumulation of cells. This phenotype is highly characteristic of tumor formation in multicellular organisms.

In designing a system to target abnormally-absent apoptosis, one can consider two approaches. One could identify a key anti-apoptotic factor that requires down-regulation or, conversely, target a pro-apoptotic factor that requires up-regulation. For the former, one might consider X-linked Inhibitor of Apoptosis (XIAP), which, while not present on the above figure, is responsible for inhibiting caspases (Vucic and Fairbrother, 2007). Caspase activation in the apoptotic pathway can be considered to be a point of no return, a trigger for the irreversible decision to undergo cellular suicide. Downregulation of XIAP should thus enable commencement of apoptosis. Alternatively, mutations in the gene encoding p53 have been cited to exist in (Toledo and Wahl, 2006).


-extrinsic pathway in mammals relies on cell-surface communication -death receptors such as Fas, DR5, or TNF receptor-1 bind to their respective ligands and recruit adaptor FADDand caspase-8 => activation of caspase-8 => activation of caspase-3 and caspase-7 Note that IAP (Inibitor of Apoptosis) proteins inhibit the caspases, so they are potential targets for cancer therapy and also appear to be perfect targets for our limiter : ) -this is especially true for human XIAP, which is a potent inhibitor of apoptosis and binds to at least three different caspases -XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, which are released from the mitochondria - AKA: API3; ILP1; MIHA; XLP2; BIRC4 - Fas pathway, inhibited by Smac, which is activated by Bax and Bak (from science’s signaling page)

  • Vucic -The IAPs as Therapeutic Targets in Cancer-

check out references 32-35 and 38-40 for more info on how IAPs relate to malignancies check our references 41-43 for more info about how XIAP confounds proapoptotic signals -could conceivably use the up-limiter to increase XIAP expression -alternatively, could up-regulate the factors that cause Smac/DIABLO and Omi/HtrA2 release from the mito Another possible target for down-regulation is Bcl-xL, which prevents the release of cytochrome c into the cytoplasm -activated by STAT3,5 Interestingly, XIAP is turned off by the expression of Bax and Bak (which inhibit Smac) and it inhibits capsase 3 while Bcl-xL is inhibited by caspase 3 and in turn inhibits Bax and Bak (Science signaling) -thus, inhibition of XIAP will result in inhibition of Bcl-xL via caspase 3, both of which will result in promoting apoptosis. Could also target Bax or Bak, since high levels of both will also result in decrease in levels of XIAP and Bcl-xL

-might even want to target both, seeing as they operate at different levels of the apoptosis pathway (Bcl-xL before cytochrome c release and XIAP afterwards)

Apoptosis in yeast

While still an ongoing debate, there is increasingly more evidence that yeast undergo programmed cell death. Despite the fact that there seems, that yeast undergo a similar programmed cell death


  • medical

Research

Carcinogenesis is characterized by the

Through an intricate balance between oncogenes, which are described for their ability to result in a cancer phenotype when overexpressed


With respect to its role in the cancer phenotype, two theories dominate the discussion about the relationship between


References

1. Toledo and Wahl, Regulating the p53 pathway:in vitro hypotheses, in vivo veritas, Nature Reviews vol 6. 2006

2. Vucic and Fairbrother, The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer, Clin Cancer Res. 2007;13(20)