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.

Cellular suicide and the cancer phenotype

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

In response to either stressful circumstances or communication from neighbors, cells will often undergo a highly regulated process that results in cell death. This process is known as apoptosis or programmed cell death. 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, such as oxidative stress or UV treatment.

The genetic underpinnings that encode for apoptosis include changes to multiple nodes in the robust network of pathways.

In general, it can be said

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.

It should come as no surprise, then that multiple disease states are defined by

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

Apoptosis is highly regulated according to an ongoing balance between that

When a normal apoptotic response, often by mutations to , cell proliferation can occur unchecked.

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

-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 are increasingly more signs that yeast undergo. Despite the fact that there seems, that yeast undergo a similar programmed cell death

• medical

Research

References

• directed evolution (includes epigenetics?)