Team:BrownTwo/Limiter/utility

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<p>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.</p>   
<p>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.</p>   
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<p>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.</p>
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<p>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.</p>
=Cellular suicide and the cancer phenotype=
=Cellular suicide and the cancer phenotype=
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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.  It is possible to identify a key anti-apoptotic factor that requires down-regulation or, conversely, to 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 help initiate apoptosis.  Alternatively, mutations in the gene encoding p53 have been found to exist in 50% of cancers (Toledo and Wahl, 2006).  These mutations occur overwhelmingly in the DNA binding domain of this protein, thus disabling its ability as a transcriptional regulator.  Since the inhibition of apoptosis stems from a defective p53, it might be necessary to introduce a protein into the cell with analogous activity to p53.  Upregulation of this exogenous genetic input would then result in apoptosis.
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In either situation, it is essential to keep in mind that the maintenance of factors that promote and inhibit apoptosis defines a healthy cell. Any regulatory system set in place must respond appropriately to apoptotic stimuli, and should otherwise exist passively in the system when no regulation is needed.  These considerations emphasize the need for a limiter-type regulatory device.
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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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-extrinsic pathway in mammals relies on cell-surface communication
 
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-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
 
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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 : )
 
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-this is especially true for human XIAP, which is a potent inhibitor of apoptosis and binds to at least three different caspases
 
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-XIAP is inhibited by Smac/DIABLO and Omi/HtrA2, which are released from the mitochondria
 
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- AKA: API3; ILP1; MIHA; XLP2; BIRC4
 
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- Fas pathway, inhibited by Smac, which is activated by Bax and Bak (from science’s signaling page)
 
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*Vucic -The IAPs as Therapeutic Targets in Cancer- 
 
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check out references 32-35 and 38-40 for more info on how IAPs relate to malignancies
 
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check our references 41-43 for more info about how XIAP confounds proapoptotic signals
 
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-could conceivably use the up-limiter to increase XIAP expression
 
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-alternatively, could up-regulate the factors that cause Smac/DIABLO and Omi/HtrA2 release from the mito
 
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Another possible target for down-regulation is Bcl-xL, which prevents the release of cytochrome c into the cytoplasm
 
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-activated by STAT3,5
 
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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)
 
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-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
 
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-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=
=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 to suggest that yeast have apoptosis as well (Frohlich et al., 2007).  Despite the fact that apoptosis seems to make most sense in a multicellular context, the organisms nonetheless show signs characteristic of a programmed cell death.  In fact, much research about apoptotic pathways from mammals can be conducted in yeast, due to the fact that many of the genes and pathways present in mammals share homology to those found in yeast.  Given this promising range of homology, one might consider first applying the regulatory approach discussed above for mammals in a yeast framework.  A limiter device in yeast could also serve as a useful tool for understanding important nodes in the apoptotic network.
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*medical
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=References=
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<br>1. Frohlich et al. Yeast apoptosis—From genes to pathways. ''Seminars in Cancer Biology'' 17 (2007) 112–121
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<br>2. Toledo and Wahl, Regulating the p53 pathway:in vitro hypotheses, in vivo veritas, ''Nature Reviews'' vol 6. 2006
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<br>3. Vucic and Fairbrother, The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer, ''Clin Cancer Res.'' 2007;13(20)
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=Research=
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=References=
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*directed evolution (includes epigenetics?)
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Latest revision as of 16:34, 8 November 2010



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.
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