Requirement of Rsk-2 for Epidermal Growth Factor-Activated Phosphorylation of Histone H3
Corsi, C.A. et al. (1999). Science 285: 886-891.
In this paper, the authors reveal an interesting mechanism by which growth factors (peptides released by one cell the tell another cell [or sometimes the same cell] to grow) regulate gene expression. It had been previously known the epidermal growth factor (EGF) can induce gene expression (thus inducing the synthesis of new proteins, or increasing the number of already existing proteins) via the Ras-MAPK pathway. Now, I do not want to go into detail about how this pathway works, but if you are interested you can check out my other web site where I talk about it in more detail. Let me just say that this is a signaling cascade where the activation of one kinase (a protein that adds a phosphate group to another protein in a processes called phosphorylation) leads to the activation of another kinase. The "end" kinase in this cascade is MAPK (Mitogen Activated Protein Kinase), sometimes called ERK (Extracellular Regulated Kinase). When MAPK is activated, it can then phosphorylate and activate other kinases (such as Rsk-2) as well as translocate into the nucleus to phosphorylate and activate transcription factors (proteins that bind to DNA and activate gene expression).
So, what are they trying to do in this paper? I mean, it sounds like it's all worked out, right? Not entirely. In addition to the activation of transcription factors, other events need to occur for gene expression to occur. Remember, your DNA is really long! It's been estimated that the DNA in one cell is about 1 meter long. So, how can your cell pack all of that into one tiny nucleus? It does so by binding the DNA tightly with protein, a structure called chromatin. Now, if the DNA is so tightly bound with the protein (called histones), how can the transcription factors and other proteins involved in gene expression have access to the gene? Well, the cell needs to modify how tightly the DNA is bound to the histones. It does this by modifying the histones directly (either adding phosphate groups, acetyl groups, or methyl groups). By modifying these histones, the DNA in that particular region become less tightly bound, and now the proteins involved in gene expression have easier access to the gene!
Now, can we tie all of this together? In other words, how does EGF (or other growth factors) modify histones? In this paper, the authors show that Rsk-2 (one of the proteins activated by MAPK) can phosphorylate one of the histones. This correlates well the expression of the particular genes in that region also. Pretty cool, eh? In fact, in cells with Rsk-2 mutations (taken from human patients with a disease called Coffin-Lowry Syndrome [CLS], caused by a mutation in the gene for Rsk-2), EGF is able to induce cell cycle progression (so Rsk-2 phosphorylation of histones is not totally necessary for this event), but is unable to phosphorylate the histones and activate some transcription factors regulated by Rsk-2. To further substantiate that Rsk-2 is the protein involved here, they added normal Rsk-2 to the CLS cells and found that now EGF can lead to histone phosphorylation!
Okay, now this might be difficult to understand how this seemingly pure cell biology paper can be important to you, but I think it is. Why? Well, the regulated expression of certain genes underlies many aspects of cellular biology, many of which have important consequences for all of us. For example, development, learning and memory, and drug addiction are all consequences of regulated gene expression. Further, problems in gene expression may play important roles in a variety of diseases as well, such as cancer. Therefore, understanding how the cell normally regulates gene expression may help us better understand normal cellular biology as well as explain various diseases. I hope I'm not losing anyone here!
So, why this paper? Well, I've noticed that chromatin remodeling is a very hot topic right now. People have known for some time that different stimuli can lead to modifications of histones (e.g. phosphorylation, acetylation, and methylation), but it hasn't been until recently that scientists have really been able to fit this into the puzzle of gene expression. So, I expect that the momentum in this field will not slow any time soon. Thus, I thought it might be interesting to include this paper on this site to give you a taste of what may lead to important discoveries in the future, especially as it pertains to treating different diseases.
One more note, a very interesting review (much more advanced than what I have here) came out recently, and I would highly suggest anyone who would like to learn more about this exciting area to look it up. The author is Michael Hagmann, and the citation is "How Chromatin Changes its Shape" in Science 285: 1200-1203 (1999). He points out one interesting finding that I will add here, if you don't mind! So, the paper above looks how the phosphorylation of one of the histones (H3 if you're interested) leads to increased gene expression of genes involved in the growth factor response. So, this phosphorylation opens up the chromatin allowing the transcriptional machinery access to the genes. Well, this exact same site is phosphorylated also in M phase (the above paper looks at G1 phase...you can check out my cell cycle website for more information about the various phases of the cell cycle), however this phosphorylation induces chromatin-condensation (which means that the chromatin actually becomes even more tight!). Thus, the effect of this phosphorylation seems to depend on the phase of the cell cycle (probably because different proteins are activated): in G1, the chromatin opens up and in M, the chromatin closes up. Cool, eh?
Okay, I hope I kept all of you this far...if I did, I'll consider that an accomplishment itself! Mostly, I'm trying to keep this website more basic, but sometimes I come across a cell biology paper that I just think is really cool! I hope you don't mind! Thanks again and visit back real soon!