Showing posts with label CLL. Show all posts
Showing posts with label CLL. Show all posts

Sunday, November 10, 2013

FROM C-AMP, as an Immune modulator, TO COMPLEX LYMPHOPROLIFERATIVE DISORDERS

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!
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THIS IS HOW THE CELL GOES FROM A SIMPLE C-AMP TO COMPLEX ACTS OF SURVIVAL VERY RAPIDLY!

Friday, April 19, 2013

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor

*T-cell therapy, that is genetically engineered T-cells, is a valid modality of cancer treatment.  Porter et al updated their finding at the ASH describing response rate in refractory CLL and ALL.  Patients were given a lentiviral vector that expressed a chimeric antigen receptor "with specificity for the B cell Antigen CD19 paired with CD137 and CD3-zeta." (hemonc today) some of the reported results where positively dramatic.
The experience with MAGE 11 for treatment refractory melanoma did not go so well.

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor 

What you pick to attack should not be in the brain (attack to the brain by T cell is likely), and involving a "crazy gene" the like of Androgen Receptor will have many unexpected consequences.  patient died with coma and seizures!   T-cell tissue penetration is bound to occur because it is what T cell do so your task is to pick the receptor carefully!

and don't go out there and pick p300, a potent and ubiquitous transcriptional regulator, because it is Ubiquitous!  Tissue specificity as done above in Hematologic malignancies would be more appropriate!
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NOW A BIT OF GOOD NEWS

Infusion of Autologous dendritic cell Immunotherapy  (AGS-003) given with SUNITINIB extended survival in Metastatic Renal cell cancer!   Think Immunotherapy when the going get tough we told recently... congrats to NC researcher to have proven the point!   Follow this principle in tough Myeloma cases.  May be drendritic cell infusion will work in Myeloma!