REVISITING THE FIRST LAW OF NATURE AND IDENTIFYING THERAPEUTIC TARGETS.

As we proposed earlier, there are major forces in the cell that once unleashed drive cellular metabolic pathways in certain direction to preserve life. We coined these laws of nature because they cannot be changed fundamentally.  The first one is that DNA aberrancies will trigger activation of P53 and stoppage of cell cycle to allow correction.  If those corrections are insufficient, cell death is triggered both downstream (toward the nucleus), but also upstream (toward death receptors).  Indeed, one of the ways the P53 leads to cell death is through modulation of death receptors to induce the Caspase 8 machinery of programmed death.

Modulation of Death receptor is an interesting phenomenon.  it goes to the basic notion of sensitization and desensitization.  Dilute active receptors and you have less effect.  Death receptors once stimulated usually by Tumor Necrosis Factor, lead to Caspase 8 activation (through FADD dependent or independent route).  To decrease the chance of Random stimulation of Death Domains, the cell makes Decoy Receptors which divert the stimulant toward them instead of the Death Domain.  The more the decoy or mimic receptors, the less the chance the stimulant will reach the Death Receptor (DR).  The best Dummy (Decoy) Receptor does not have any intracellular portion of the Receptor, therefore no induction of intracellular signals is initiated. Another protection is the Silencer Of the Death Domain (SODD) which does exactly what its name says!
Toning down the TNF machinery is one of the modulation mechanism.

4 important observations:

1.  Activated Caspases attack
-laminins reportedly leading to Nuclear Shrinkage and Chromatin condensation
-destroy inhibitors to Endonucleases release leading to further DNA Break down
-MOST importantly, Caspases attack the Cytoskeleton (Actin, Pletin, ROCK1, Gelsolin,Microtubules and all filamentous structures, THIS TRIGGERS THE UNFOLDING OF THE 2ND LAW OF NATURE WITH LIBERATION OF CYTOCHROME C FROM THE MITOCHONDRIAL MEMBRANE INTO THE CYTOSOL, AND ACTIVATION OF CASPASE 9 AND ALL SUBSEQUENT CASPASES, SETTING AN IRREVERSIBLE COURSE TO PROGRAMMED DEATH.

2. You note that the 2nd law is downstream the 1st law, therefore targets driving the 2nd law will bypass the mechanisms of resistance in place to stop the progression of the 1st law.  This includes the Bcl-2.

3.Many targets are located here in the functions of Death Receptors.  These include the Receptor itself (CD95),  but they also include CD 120, AP03, P55, P60, P75 (NERVE), C-JUN (STRESS), FADD, APO2L, AND OF COURSE THE SILENCER (SODD).

4. The gene encoding the Death Receptor and several Decoys has been traced to 8p21-24.  THE QUESTION IS, WILL PRESENCE OF MUTATION OF 8p PREDICT FOR RESPONSE TO INTERLEUKINS, INTERFERON OR TO SOME BIOLOGIC INTERVENTION?  IS OSTEOPROTEGERIN (8q23-24) PRESENCE SUCH A PREDICTOR?

FOR BASAL CELL LIKE BREAST CANCER PATIENTS, IS MYC  (8q24.12) PRESENCE A SIGNAL THAT TUMOR GROWTH FACTOR ARE THE MAIN DRIVING FORCE?  IS AVASTIN AND RELATED ANTI-GROWTH FACTORS IMPORTANT IN THE THERAPEUTIC STRATEGY?

WE ARE HARD AT WORK AT CRBCM!