Tuesday, January 29, 2013

COMPLICATIONS ENCOUNTERED AT DEFINING GENE AMPLIFICATION.

As we dig deeper into the 4th law of nature, we quickly encountered difficulty in defining primary and secondary amplification.

Primary gene Amplification:
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It is now evident that an amplified gene could be the result of the effect of a growth factor or cyclins acting on a receptor at membrane level  and into the Cytosol.  This is a secondary gene amplification.
Once a cell has chosen a specific orientation, that is it has chosen between proliferation or differentiation, that orientation will be the focus of gene Amplification.  This amplification is generally non specific and is our definition of Primary Amplification.  This general amplification is generally mild like in a buzz.  when found, it is low level amplification. the gene is found generally in less than 10 percent of cells... Most of the time around 4-5% of cells.  It is a tone.  Our research locate this Amplification in the MLL and MYC genes and in the Histone Acetyl transferase and related molecules (PCAF, P300).  Sometime, this basic amplification and a secondary amplification can double up in the same gene, leading to an exacerbated amplification such as it occurs in Burkitt lymphoma.  This will prompt us to look into difference of Expression of MYC in Ovarian cancer Vs Myc expression the Burkitt lymphoma.  There must be a big difference, may be in the level of Cyclins.  we will investigate.

Suffice is to say the real reason of the Amplification to be in the MYC and Histone Acetyl transferase, is that both have regulatory powers on the P53 which needs to be downregulated to allow proliferation to continue in cancer.  So aside from the Regular MDM2 which the principal regulator, Histone acetyl transferase which MYC promotes, is the second main P53 regulator.  In our previous blog, we had discussed the interactions of P53 with upstream structure toward the membrane.

Secondary gene Amplification.
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 Secondary gene Anplification is the result of the action of proliferation genes,  Amplification gene and oncogenic driver and non driver  Mutations.
This Amplification targets
1. Membrane receptors (EGFR, FGFR-1, Her-2,)
2. RAS and GTPases (ie. RAp1GTPase, Hras)
3. growth factors and CYCLINS  (CCND1,FGFR and its related HST-1,c-MET)
4. Signal trasduction pathways (AKT/MTOR)
5. Regulators of pathways (TSG with impact on the AKT)
6.Transcription Factors (MLL, a regulator of transcription factor with activity on the TSG in the AKT/MTOR pathway
7. Histones and epigenetic triggers
8. DNA proper  (Ki 67 seen only in dividing cells, CDKs,  it may acts also on genes of differentiation such Myo, RET, TRK, int-1, hst-1 )
 Secondary amplification double up on the primary to multiply itself.

Some other Amplifier are downregulated for action to be unveiled (PTEN and its increase of AKT)
SECONDARY GENE AMPLIFICATION WILL TEND TO BE WITH HIGHER PERCENTAGE THAN 10% 

A note to make before
Downstream from MTOR is located a key to Apoptosis by the name of FOXO, check it out!  THE FOX HIDE THE PUMA GENE!
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