Fifty years ago, in the early days of biology, so little was known about the cell that all of the proteins outside of its nucleus were grouped into one big "cytoplasmic soup." Now, as the list of known cellular ingredients continues to expand beyond the capacity of any recipe card, two Rockefeller University scientists are taking a step back to ask whether there might be a better way to organize the current thinking about a particularly important class of proteins inherent to all living cells.
In the Feb. 1 issue of Science, James E. Darnell, Jr., M.D, and Ali H. Brivanlou, Ph.D., propose a reclassification of all known transcription factors - an essential group of over 2000 proteins responsible for turning genes "on" or "off." Their proposed schema is the first-ever ordering of transcription factors based solely upon the role these molecules play in the cell.
"Our aim in this paper is to provide a framework with sufficiently few functional categories of transcription factors so that students and researchers have some chance to remember all the important groups. We also believe this teaching aid is based on sound cell physiologic principles," says Darnell, head of the Laboratory of Molecular Cell Biology at Rockefeller University and co-author of the popular textbook, "Molecular Cell Biology."
"We need a global perspective such as this in order to form new ideas about how cells deal with the necessity to change transcription rates," says Brivanlou, head of the Laboratory of Molecular Vertebrate Embryology at Rockefeller.
Transcription is the process by which cells "read" their genetic instructions: DNA is "transcribed" into RNA, which is then converted into protein. Specific proteins in the cell called transcription factors control which genes are read and which ones are silenced, thereby dictating everything that goes on in a given cell at any moment. Well-studied transcription factors include p53 and the Smad and STAT proteins, all of which play a major role in many cancers.
Because transcription goes awry in many diseases, including cancer and viral infections such as HIV, a better understanding of how cells "read" genetic instructions may lead to new drug therapies for these diseases.
Previously, transcription factors were grouped by scientists according primarily to their physical structure as determined through X-ray crystallography. However, all of the proteins in one structural group don't necessarily operate in similar fashion physiologically.
"Jim Darnell and I realized that it makes more sense to think about these proteins in terms of their behavior instead of their structure," says Brivanlou.
The two scientists first began discussing this issue with students during a course Darnell was teaching Rockefeller University. The title of the course was "gene expression" and included discussions of the various ways in which the cell receives instructions from the outside and then responds to these signals by altering the production of specific proteins, or, in scientific terms, the "expression" of certain genes. These signals include primarily hormones (e.g., estrogens) and small proteins (e.g., growth hormone). Transcription factors are the mediators of these signals and ultimately govern which genes are expressed.
Darnell and Brivanlou realized that by grouping transcription factors according to how they are signaled or controlled, they could more readily recognize global patterns, such as evolutionary relationships between groups of transcription factors.
Yet the new classification is not meant to be an end in itself, according to the scientists. "This is not a Unified Law of Transcription Factors," jokes Brivanlou.
Darnell adds, "We know that some of these groupings may be controversial, but we think there are good reasons to classify groups the way we have. For example, all of the factors that respond to extracellular protein signals are very disparate in their internal activation pathways but all share a global design: cell surface stimulation by an extracellular protein that activates a latent cytoplasmic factor which upon activation enters the nucleus to function in activating gene transcription."
The researchers hope the paper will foster vigorous discussions about how to best organize these important proteins and ultimately lead to new and important concepts about the workings of the cell.
The Darnell and Brivanlou laboratories are supported largely by the National Institutes of Health.
John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of which are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller - the nation's first biomedical research center - continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.
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