This month's newsletter includes a new feature that we call Journal Club.  In this column, I will discuss a recent manuscript

Steven R. Ellis, PhD Research Director

I thought I would begin this forum with an article that many of you likely haven't seen, mostly because its relevance to DBA may not be immediately obvious.  The article is entitled "An ARF-Independent c-MYC-Activated Tumor Suppression Pathway Mediated by Ribosomal Protein-Mdm2 Interaction" by Yanping Zhang and colleagues, published in Cancer Cell 2010 18:231-243.

My reason for choosing this article most likely reflects my role as a college professor and my desire to be able to understand and explain, 'why things are the way they are.'  The manuscript by Zhang and colleagues provides a potential rationale for the mechanism of cell death induced by mutations in genes encoding ribosomal proteins.  This mechanism of cell death appears to involve a protein known as p53, which gets activated in cells where ribosome synthesis is disrupted.  A search of the pubmed database reveals there have been over 55,000 papers written on p53.  This interest in p53 reflects its role in suppressing tumor formation through a variety of different mechanisms.  On the flip side of tumor suppressors like p53 are oncogenes, or genes that promote cancer.  A very important oncogene is c-Myc.  In contrast to p53 which can block cell division or induce cell death, c-Myc promotes cell growth and division, in part by stimulating ribosome synthesis.  Thus, the ribosome is in a pivotal position between the oncogene c-Myc and the tumor suppressor, p53.

Zhang and colleagues hypothesized that p53 activation in response to a dys-regulation of ribosome synthesis brought on by c-MYC overexpression could be a natural mechanism to eliminate cells with a high potential to become tumorigenic.  They tested this model by disrupting the signaling pathway between dys-regulated ribosome synthesis and p53 activation.  Their findings revealed that c-MYC induced tumorigenesis was enhanced in the absence of this signaling mechanism supporting their hypothesis (see Figure).

So what does this tell us about DBA?  Basically, the signaling mechanisms studied by Zhang and colleagues are very similar if not identical to signaling mechanisms thought to be in play in cells where mutations in genes encoding ribosomal proteins interfere with ribosome synthesis.  Thus, mutations in ribosomal protein genes could trigger cell death by unfortunately spilling over into a mechanism hard wired into cells to reduce tumor formation (see Figure).  So, a cellular mechanism that presumably helps all humans reduce tumor incidence may be the culprit affecting those unfortunate enough to back into this mechanism through an inadvertent mutation in a gene encoding one of the ribosomal protein genes involved in DBA.      

My reasons for choosing this article could be considered something of a selfish academic pursuit, since speculating on 'why things are the way they are' is not everyone's cup of tea.  So, at this point I will take the advice of a minister friend of mine, who once told me never finish a sermon, or article as the case may be, without providing the good news.  The good news in this case is that the research community studying cancer is very large and that by spilling over into mechanisms relevant to those studying cancer, DBA has caught the eye of an increasing number of outstanding researchers.  Some of these researchers have turned their attention to DBA, adding to the cadre of researchers already in the field.  As interest in DBA research grows, so do the prospects for continued advances in the field and for improved therapies arising from these discoveries.