WORCESTER, Mass. -Investigators from the University of Massachusetts Medical School (UMMS) Department of Cell Biology and the UMass Memorial Cancer Center approach a critical, mechanistic link between cell fate, proliferation and growth control in a paper published in this week's issue of Nature.  Although researchers have long appreciated the coordination between these important components of biological control, the specifics of their "cross-talk" have not been understood. Now, in "Mitotic occupancy and lineage-specific transcriptional control of rRNA genes by Runx2," the UMMS scientists describe a breakthrough in resolving this important question, defining essential parameters of cell function that must be regulated in a cohesive manner for development and tissue renewal throughout life.  

Previous studies have demonstrated that an imbalance between control of cell fate, proliferation and growth control is disrupted during early stages of cancer and progression of the disease.  The change in regulation of these three major cellular processes provides a "blueprint for aberrant gene expression" that modifies tumor cell function.   The consequent changes in cellular behavior are conveyed to progeny cells during cell division, a process known as cell fate determination.  This occurs in association with modified control of the cell life cycle that supports proliferation and alterations in growth control that determine cell size and shape, as well as the composition of cancer cells. 

In this paper, the UMMS research team led by Gary S. Stein, PhD, Chair of Cell Biology and Deputy Director of the UMass Memorial Cancer Center, with his colleagues Professors of Cell Biology Janet L. Stein, PhD, and Jane B. Lian, PhD, and Andre J. Van Wijnen, PhD, Associate Professor of Cell Biology, utilized state-of-the-art molecular, cellular and biochemical approaches to define properties of Runx transcription factors, an important group of regulatory proteins that establish and maintain cell identity.  The investigators were primarily interested in how information for cell specialization is conveyed through successive cell divisions for regulatory events that determine cell cycle progression or exit from the cell cycle.  

Their findings establish that cell type-specific transcription factors operate through a novel epigenetic-not a modified gene, but modified control of a gene-mechanism.   They demonstrate that the factors are also associated with nucleolar-organizing regions,  specific sites of chromosomes where genes that are instrumental for cell growth are located.  The results further demonstrate that Runx transcription factors not only control genes that regulate lineage commitment and cell proliferation, but also control protein synthesis by directly regulating expression of ribosomal genes. 

The discovery that Runx2 regulates ribosomal biogenesis, which is intricately connected with cell growth, suggests that this class of regulatory factors may establish cell identity by coordinately controlling growth, proliferation and differentiation, or cell specialization.  From a broad biological perspective, lineage specific control of ribosomal biogenesis may be a fundamental function of transcription factors that govern cell fate to support normal biological processes throughout life.  Unfortunately, alterations in the function of such pivotal regulatory factors can also result in the onset and progression of changes in cell properties that are hallmarks of cancer and skeletal disease.  A greater understanding of the coordination of cell growth, proliferation and differentiation by a single regulatory factor, provides novel and very much needed options for development of targeted therapies for these devastating disorders.
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