It is well known that cyclins which include the TNF alpha will only have a full effect on inflammatory processes after depletion of c-AMP. That is for the inflammatory process to reach full effect activations of FRA-1( FosB) and C-Fos that need to occur. The mere stimulation of c-JUN which results from stress at the Receptor is also accompanied by CRE (CRE-tkCAT) increase (through the CRE-binding proteins) which, in a feedback process activates c-AMP to dampen the c-JUN stimulation. The amount of activity at c-AMP is therefore a clear modulator of inflammatory processes!
Anti -COX2 which decreases transcription of related genes, will in fact stimulate the C-JUN.
It is important to stress that as c-JUN, JUNB and subsequently c-Fos increase in number, the AP-1 complex is more formed and activated:
"The
activator protein 1 (
AP-1) is a
transcription factor which is a
heterodimeric protein composed of proteins belonging to the
c-Fos,
c-Jun,
ATF and
JDP families. It regulates
gene expression in response to a variety of stimuli, including
cytokines,
growth factors, stress, and bacterial and viral infections.
[1] AP-1 in turn controls a number of cellular processes including
differentiation,
proliferation, and
apoptosis.
[2]
AP-1 upregulates transcription of genes containing the
TPA DNA
response element (TRE; 5'-TGAG/CTCA-3').
[1] AP-1 binds to this DNA sequence via a basic amino acid region, while the dimeric structure is formed by a
leucine zipper.
[3] " wikipedia. CBPA, overexpressed in some leukemas, is a leucine Zipper!
In the JDP families is located JDP2, an inhibitor of AP-1.
Interaction of AP-1 through its ATF component will lead to activation of EP300, a gene we talked about, and which leads to cellular differentiation by its contact with the NOTCH, MAML1 and the Merlin, Again here the EP300 binds to the CREB to activate c-AMP, the immune modulator discussed.
"This gene encodes the
adenovirus E1A-associated cellular p300 transcriptional co-activator protein.
The protein functions as
histone acetyltransferase [4]
that regulates transcription via chromatin remodeling, and is important
in the processes of cell proliferation and differentiation. It mediates
cAMP-gene regulation by binding specifically to phosphorylated
CREB protein.
This gene has also been identified as a co-activator of
HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as
VEGF.
[5] wikipedia
Other virus affect JDP2, Cyclin D, and the Pim
"E1A binding protein p300 also known as
EP300 or
p300 is a
protein that, in humans, is encoded by the
EP300 gene.
[1] This protein regulates the activity of many genes in tissues throughout the body. It plays an essential role in regulating
cell growth and
division,
prompting cells to mature and assume specialized functions
(differentiate), and preventing the growth of cancerous tumors. The p300
protein appears to be critical for normal development before and after
birth.
The p300 protein carries out its function by activating
transcription. To be specific, p300 connects
transcription factors,
which are proteins that start the transcription process, with the
complex of proteins that carry out transcription in the cell's nucleus.
On the basis of this function, p300 is called a transcriptional
coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the
nuclear receptor interaction domain (RID), the
CREB and
MYB interaction domain (KIX), the
cysteine/
histidine regions (TAZ1/CH1 and TAZ2/CH3) and the
interferon
response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2
and IBiD of p300, each bind tightly to a sequence spanning both
transactivation domains 9aaTADs of transcription factor p53.
[2][3]
The EP300 gene is located on the long (q) arm of the human
chromosome 22 at position 13.2.
EP300 is closely related to another gene,
CREB binding protein, which is found on human
chromosome 16." (wikipedia)
Please note the MYB involvement:
-as it will play a role in hair discoloration,
-is downstream from the PDGF and plays a role in giving longevity to Notch dependent processes
-regulated through the miR155 in CLL
-involve Flavonoids
-involve the Avian Myeloblastosis Virus.
Note also IBiD as it modulates response to Interferon!
Please refuse to see (and I see you resisting) that P53 is engaged by this!
=======================================================
THIS IS HOW THE CELL GOES FROM A SIMPLE C-AMP TO COMPLEX ACTS OF SURVIVAL VERY RAPIDLY!
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