The Hedgehog, Ptch1, AND the Gli zinc-finger transcription factors

If there is an example where GENE INTERFERENCE could have a meaningful impact, it is in this pathway like a deluge of gene activations.  The impact could extend from Basal cell to bladder cancers to Gliomas!

"PTCH1 is a member of the patched gene family and is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product, is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgheog binds PTCH1, smoothened is released and signals cell proliferation." wikipedia.

POLIZIO ET AL
 The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis in normal physiology, and its dysregulation is a common theme in cancer. The Hh ligands (Sonic Hh, Indian Hh, and Desert Hh) bind to the receptors Patched1 and Patched2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a seven-transmembrane protein, which was only recently shown to function as a G protein–coupled receptor (GPCR) with specificity toward the heterotrimeric guanine nucleotide-binding protein G_i. In addition to activating G_i, Smo signals through its C-terminal tail to inhibit Suppressor of Fused, resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to so-called "canonical Hh signaling."

WHEN YOU TALK ABOUT ZINC-FINGER YOU KNOW YOU ARE TALKING ABOUT HISTONE MODULATION AND DIRECT DNA INTERACTION, ALL OCCURING MOSTLY THE EPIGENETIC ZONE MOSTLY!  THEREFORE THIS COULD EFFECT EVEN THE LEUKEMIAS!
THE CRBCM IS TAKING A CLOSER LOOK!

"Gli regulation by the opposing activities of Fused and Suppressor of Fused

Maximilien Murone^{1,2ET AL!}

Hedgehog (Hh) proteins are secreted factors that control cell proliferation and cell-fate specification¹. Hh signalling is mediated in vertebrates by the Gli zinc-finger transcription factors (Gli1, Gli2 and Gli3) and in Drosophila by the Gli homologue Cubitus interruptus"

OTHER GENES IMPLICATED!

PTCH1 gene

WNT3A

IRF6

GLI

TGF-beta

TrkC: Neurotropin -Receptor

AND THE DANCE OF GENES CONTINUE!

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.<sup>[5] wikipedia



Other virus affect JDP2, Cyclin D, and the Pim</sup>


"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!

THE CRCBM RECOMMENDS THIS PIECE OF ARTICLE TO ALL READERS!

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

1. Sonja Loges*,
2. Thomas Schmidt* and
3. Peter Carmeliet⇓

+ Author Affiliations

1. Vesalius Research Center (VRC), Leuven, Belgium

1. P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium Email: peter.carmeliet@med.kuleuven.be
2. -----------------------------------------------------------------------------------------
3.  
4.  
5. Suffice is to say that the concerns mentioned in this review, which is an excellent review, unveils in pretty good details the insufficiency of a monotherapy attacking an essential function of the cells. Not only will the cell have an answer such as dummy receptors, secondary amplification of transcription factors of growth factors, but escape mechanisms that include escape of the area leading to metastasis.  I should confess that recruiting other cells to help fight the attacker (Myeloid and endothelial cells) showed clearly how much angiogenesis is globally needed.  I would think that the reaction by the NF-kB would be sufficient; with its secondary growth  factor production, induction would be the predictable way.  But clearly, the cell wants restoration of the angiogenic function and finally wins, making Avastin effects short lived.  By inducing Hypoxia, stress becomes a secondary impetus and c-JUN enters the dance and fights again with resulting amplification of growth factor and various dislocation of various cyclins at integrin locations including the Angiopoietins.
6. One of the things that needs to be emphasized or not looked at or discussed in your piece are events happening at the MEK.  You know by now that MEK is clearly amplified either by the cancerous process or in reaction to the blockage or consumption at VEGF.  Tracking MEK is important, because if amplified and mutated it may reverse mesengial transformation and render the cell more omnipotent.  It may be at the center of the observation that blocking both EGFR and VEGF reduces the progression free survival. Events at the MEK need to be scrutinized.
7. You also realize that, in the long run,  MTOR will be secondarily stimulated leading to Telomere preservation (stabilization) and cell surviva
8. The quick restoration of the angiogenic function after cessation of the treatment marks the importance of VEGF.

Your discussion has not only brought up in details the predicted failure of mono-target-therapies, but in the case of an important/critical cellular function being impaired by Avastin, and the resulting multitude of cellular responses. I really thank the authors for this important piece!
Clearly, Avastin is never meant to be a monotherapy, that is the answer!  To all action, there is a reaction. And cells expect action, it is built for them!