POLYUBIQUITINATION
The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins. To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal. The anti-proteasomes in effect block this plan. And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways. Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth? Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think? Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?
Showing posts with label proteasome. Show all posts
Showing posts with label proteasome. Show all posts
Thursday, January 17, 2013
Saturday, December 15, 2012
AT A CHECK POINT IN CELL DIVISION 2 MAIN THINGS HAPPEN:
1. DNA is checked for mistakes and corrections are undertaken.2. Chromosome segregation to eventual daughter cells is checked to avoid uneven distribution of the chromosome.
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.
The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.
When all this is going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).
This last event seems to rely heavily on activity on unattached chinetochores where check point proteins (MAS 1 & 2, UB1 etc.) accumulate and block the APX (Anaphase promoting complex) until the checking is completed and Cyclin B and Securins are ubiquitinated and destroyed to release the check hold and allow mitosis to proceed.
The need for ubiquitination of Cyclin B elevate the role of Proteasome. That is why Antiproteasome appears very important in hematologic conditions where signal transduction and subsequent cyclin activity are the driving forces toward multiplictaion of cancer cells as we stated.
When all this is going on, the cancer cell is at its weak point. That is why chemotherapy, particularly the Taxanes and the Vinca-alkaloids, is more effective. It not only disturbs the microtubule (inducing the 2nd law), but also breaks the actinic anchors to the cytoskeleton of membranes and cellular matrix causing the "Anoikis" like phenomenon within the cell. Lesion to actin like molecules (anchors) within the central nervous system could lead to neuropathy. As we know it has the side effect of these drugs (proof of concept to follow).
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