Phorbol Esters and DHT

[hedgehog_info]

Anybody understand this (Phorbol Esters and DHT) relationship. I have found a few articles but some ideas seem to be conflicting.

 

[Guest]

Post link to articles then

 

[hedgehog_info]

I was only trying to make a few correlations between these two studies...

Phorbol ester causes ligand-independent activation of the androgen receptor
http://www.blackwell-synergy.com/doi/pd ... ookieSet=1


Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli.
http://www.ncbi.nlm.nih.gov/entrez/quer ... get=_blank

I don't understand very much about androgens and its receptor but have read that it has been linked to Alopecia.

Now i have studied the Hedgehog pathway extensively and a new article came out stating that a phorbol ester can inhibit the hedgehog pathway. So i googled "phorbol ester and DHT" and came up with few articles. If some new ppl don't know here the Hh pathway is being looked at by P&G to help treat Alopecia.

This new articles hint at a little cross talked between the Hh pathway and the androgen receptor via protein kinase C. When phorbol ester is present the androgen receptor is expressed and also helps to inhibit the Hh pathway. Which turns off hair cycle by inhibiting Adult Stem Proliferation or more importantly the Growth Phase of the Hair Cycle.

Kinda interesting.

 

[Guest]

So this phorbol ester, if it is a ligand that activates the androgen receptors (scalp only?), then couldn't we just get the structure of it and make a competitive inhibitor?

 

[hedgehog_info]

Maybe but you don't want to leave the Hh pathway turned on...



12-Otetradecanoyphorbol-13 acetate (TPA) also known a phrobol ester.

 

[Guest]

I'm not familiar with teh Hh pathway, but as I read in the abstract of the second article you posted, it has something to do with cancer. What kind of cancer? Also is the Hh pathway using the phorbol ester as the primary messenger binding to the androgen receptor? Or does the Hh signal transduction pathway use another receptor that binds the receptor to provide the pathway to start via some G-protein coupled receptor mech (or some other sig transduction mech).

 

[hedgehog_info]

What kind of cancer?

Yes the Hh pathway is implicated in a wide variety of cancers. Pancreatic, Lung, BCC, Brain, Prostate and Breast to name a few big ones. Genentech just started Phase I clinical trials with a systemic Hh inhibitor

I assume it is the same phorbol ester because it targets the same kinase. The Hh pathway starts at protein called Patched and then goes to another protein called Smoothened. Protein kinase C (PKC) (which is activated by phorbol ester) is down stream off a few other steps in the Hh pathway but looks like it is just upstream of Gli (A zinc finger transcriptional activator and repressor). PKC in the Hh pathway causes the Gli proteins to turned into repressors of target genes. The Hh pathway is often called a master switch for major cellular decisions such as cell fate, angiogenic and growth factors.

I just found it interesting that this phorbol ester also causes upregulation via protein kinase C of the androgen receptor...

Here is an old diagram of the Hh pathway

http://www.biocarta.com/pathfiles/h_shhPathway.asp