Tuesday, October 13, 2015

SUMO E2 ligase is necessary for RAS/RAF oncogenesis

Just when you think a story can't get any more complex, biology up and surprises you!

This paper isn't brand new, but I don't check PNAS as often as some of the other purely -omics oriented journals. The paper in question is from Bing Yu et al., and is available here and is open access.

Its a cool story, too.  There are really no targeted chemotherapies out there that will work on KRAS specific cancers. The function of the various GTPases and their pathways are complicated and convoluted. When they are working right they are supposed to function in signaling by GTP to GDP conversions.  This communication system is so critical to normal cell functioning that disregulating of these proteins has the nasty outcomes of the cell dying or becoming a cancer cell. As in any biological system, its certainly more complex than this, because years of work with these things comes up with a whole lot more info and no clear simple answers.

This is where we come in. Turns out that this group did a big shRNA screen (this is where you transfect cells with a great big mixture of Single Hairpin RNA that knocks out RNA production (and therefore protein production) on a huge scale. The readout is typically a phenotype. In this case, I'm assuming what they did (I'm sure its in the paper. not my area of expertise.) was see what cells did or did not become cancerous and then go back and figure out what gene they knocked out.

Of the many observations they came with 2 ligases that are the only ones known to be involved in the SUMO E1 and E2 pathways (controlling the SUMO PTM, not sure if I have the nomenclature 100% correct here). Anyway...SUMOs are small proteins that are ligated to big proteins and modulate their function as post-translational modifications (PTMs). There are bunch of them and a bunch of pathways, but here you have two major regulators of SUMOylation (more info on this PTM here) that are somehow implicated in KRAS oncogenesis? Tell me more!

So, they go in and construct an RNA interference to directly deplete these SUMOylation ligases (the things that attach the SUMO PTMs) in some cells that are crazy KRAS cancer cells. Turns out that if you can't produce these proteins even a KRAS cancer cell gets subdued. Then they study it by labeling some of the cells with SILAC and repeating the knockdowns to try to figure out the mechanism by which all this is happening and come up with a group of proteins they call KASPs which is short for KRAS Associated SUMOylated Proteins that are involved in this mechanism.

To sum up: We start with a common cancer mutation we don't have drugs for and we figure out a protein, not just that, a whole series of proteins that may be potential targets for treatment when someone has this type of cancer. Inhibiting these proteins and maybe you have a new chemotherapy. And along the way, we learn an entirely new biological modulation pathway?

I highly recommend picking this one up. Its nice to see what we do fitting seamlessly into a biological study alongside the cutting edge tools the molecular biologists are using these days!

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