Saturday, December 8, 2012

5th Law of Nature...

5th LAW OF NATURE,  DISABLING THE FBW7/UBIQUITINATION FOR CANCER GROWTH

FOR CANCER GROWTH, THE NATURAL TENDENCY  IS FOR GROWTH OF ABNORMAL CELL.  IT IS PARAMOUNT FOR THE CANCER CELL TO PARALYZE THE UBIQUITINATION OF P53.  THIS WILL RESULT IN A NET INCREASE OF USED OR PHOSPHORYLATED P53
WHICH HAS SEVERAL EFFECTS:
(ASSUMPTIONS)

1.  BLOCKING THE BAX WAY TO CASPASE CASCADE MOST LIKELY BY NON-UBIQUINATED CYCLIN RESIDUE BUILD UP.

2.  DISABLING THE SONS OF THE SEVENLESS, ULTIMATELY PARALYZING ACTIVATED P53  LEADING TO PROGRESSION OF THE CELL CYCLE DESPITE CONCURRENT CHANGES IN DNA (FIRST LAW ESCAPE).  THIS IS ACHIEVED THROUGH IN CREASE OF PHOSPHORINATED MOLECULES NOT DESTROYED THROUGH PROTEASOMES 

3. INCREASE PRODUCTION OF MUTATED P53 LEADING TO INCREASE, THROUGH TRANSCRIPTION FACTORS, OF THE POOL OF ABNORMAL P53 RESIDUE OR INHIBITORY MOLECULES

4. C-MYC UPREGULATION WOULD BLOCK ARF, A BREAK OR INHIBITOR TO MDM2.

THIS IS WHY MUTATION IN THE MDM2 IS ONE OF THE MOST COMMON MUTATIONS FOUND IN CANCER BECAUSE IT DESTROYS OR SUPPRESSES THE UBIQUITIN LIGASE INVOLVING P53 TO FORCE CELLS INTO CYCLE EVEN IN THE PRESENCE OF DNA BREAKS AND / OR ERROR/MUTATION.

CANCEROUS GROWTH HAS TO PARALYZE APOPTOSIS MAINLY BY ALTERING CONCENTRATION OF NON-WILD TYPE P53.

THIS IS ALSO WHY ANTI- PROTEASOME DRUGS (SUCH AS VELCADE) ARE THE MOST POWERFUL DRUGS AFTER ANTI-MICROTUBULE DRUGS (SEE 2ND LAW).   DESTRUCTION OR NEGATION OF PROTEASOME PROCESSES SEEMS TO PRESERVE MOLECULES THAT CONQUER THE BAX SUPPRESSION OF BUILD UP NON UBIQUITINATED P53.

2 OBSERVATIONS FOLLOW:

1.  THIS MECHANISM IS VERY IMPORTANT IN HEMATOLOGIC CANCERS WHERE SIGNAL TRANSDUCTION ABNORMALITY IS THE DRIVING FORCE.   ARSENIC TRIOXIDE WILL HAVE A SIGNIFICANT EFFECT HERE SINCE IT ATTACKS SEVERAL AREAS RANDOMLY IN THE SIGNAL TRANSDUCTION PATHWAYS.   COMBINING IT TO VELCADE WILL HOWEVER BE MOST LIKELY TOO TOXIC.

2. A COMBINATION OF ABRAXANE AND VELCADE WILL BE THE MOST POWERFUL COMBINATION OF ALL COMBINATIONS (MAY BE WITH THE ADDITION OF ANTI-KINESIN) FOR TRIPLE NEGATIVE BREAST CANCER.(OR ANY CANCER).

PROOF OF PRINCIPLE:

1.CAN QUANTITATION OF  PHOSPHORINATED P53 BE ACHIEVED IN PEOPLE WITH CANCER (WITH MUTATED MDM2)  ?

2. SHOULD MDM2 MUTATION BE A BETTER SURROGATE FOR PRESENCE OF CANCER

3.WHAT IS THE LEVEL OF CYCLINS AND  BAX ACTIVITY IN PATIENT WITH MDM2 MUTATION.

4.MDM2 MUTATION INDUCES GROWTH FACTOR PRODUCTION (ie. tgf BETA) THROUGH
INCREASE OF RELEVANT TRANSCRIPTION FACTORS, INCREASE RECEPTORS OR DIRECT EFFECT OF NON UBIQUITINATED  P53.

5. STATUS OF THE SONS OF THE SEVENLESS IN MDM2 MUTATION.  IS MDM2 MUTATION A PROGNOSIS FACTOR IN CANCER.

AND SO ON...





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