Apr. 2, 1998 Harvard Medical School Researchers Link Viral Oncogenesis and Cell Differentiation in a Mystery Protein of the Nematode C. Elegans
BOSTON--March 27, 1998--The tiny worm that has become a darling of developmental biologists has revealed a biological function for a mysterious protein that may play a role in the growth of tumors.
In the cover article of the April 1 Genes and Development, Yang Shi, HMS associate professor of pathology, reports that the worm's version of the human protein p300 helps cells in the early embryo decide what kind of tissue to become. Shi found that p300 also is critical for determining the number of cells formed in the embryo. His finding validates earlier cell culture experiments on how viral cancer-causing proteins subvert a cell's growth.
For the first time, the study demonstrates what p300 does in a live organism. It also suggests a mechanism for how the protein might work, forging a link to histone acetylation, an area of research that has produced major advances in the past 2 years.
The paper is an example of how unlikely creatures, such as the fruit fly, the frog, or the nematode Caenorhabditis elegans, offer shortcuts toward understanding human biology. When researchers realized that many human genes exist and function in similar forms in most species--half of all human genes are estimated to have a correlate in C. elegans, for example--they decided to exploit the superior methods of genetic analysis available for simpler animals.
Shi joined the worm community because of his interest in viral oncogenesis. From earlier work, he knew that the adenovirus oncoprotein E1A disables the host protein p300. This interaction is key to E1A's ability to make a normal cell cancerous; it prevents immature cells from differentiating into mature ones.
To determine the role of p300, Shi collaborated with co-author Craig Mello of the University of Massachusetts Cancer Center in Worcester, MA, who taught him how to work with C. elegans. The two employed RNAi, a new method developed to probe the function of any protein. They injected RNA encoding a snippet of p300 into the eggs of the mother. For unknown reasons, her offspring then fail to make the protein, offering researchers a cheap and simple alternative to a genetic knockout mouse. While establishing strains of knockout mice takes months, the RNAi worm offspring can be analyzed a few days after the injection, says Shi.
The embryos amazed him. Normal C. elegans embryos develop for 14 hours, then they hatch. But Shi found no hatchlings after that time. Stuck inside their eggshells were balls of cells without intestine, muscle, skin, or mouth. What's more, these 'embryos' had extra cell growth. Researchers know that a normal C. elegans hatchling has exactly 558 cells. The embryos without p300 had about 1,000.
These findings show that, in vivo, p300 indeed plays a pivotal role in the connected processes of cell division and differentiation, says Shi. P300 acts when a cell begins to differentiate, and it does so for most of the worm's tissues.
This may provide insight into how adenovirus E1A corrupts cell growth. Shi suspects that if p300 provides the exit through which cells leave the division cycle and enter differentiation, E1A might shut this exit, trapping cells in perpetual division. Yet while p300 has been implicated in leukemia, gastric and colorectal tumors, much more research is needed to understand its possible role in cancer, Shi says.
Could the entire embryo--a shapeless lump of excess cells--be some kind of immature tumor? While this thought tantalizes him, Shi says, there is more to it. Using various markers, he found that most of the cells appear to be neuron-like.
This finding fits with vertebrate studies suggesting that most embryonic cells tend to become neurons by default. Specific signaling events are necessary to coax cells to mature into other cell types, much like it takes active signaling to dissuade a prospective male embryo from its inherent tendency to become a girl.
Moreover, a separate line of investigation is converging with Shi's research. Scientists studying gene transcription have found that certain enzymes tack acetyl groups onto histones--the proteins around which the DNA is draped. This helps initiate gene transcription. In 1996, researchers elsewhere discovered that p300 is such a histone acetylase.
Another HMS researcher, Mark Montminy, professor of cell biology at Joslin Diabetes Center, has found that p300 also interacts with CREB, a transcription factor implicated in memory, and is working to knock out a related gene in mice.
More work is needed to better define p300's modus operandi, says Shi. But he now has the tools to do that in live organisms. Yet Shi is not planning to run a worms-only laboratory. He wants to go back and forth between the nematode and mammalian cells, mindful that his ultimate curiosity lies with the latter.
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