Feb. 18, 2000 COLUMBUS, Ohio -- Researchers here have discovered that microtubules -- the subcellular scaffolding within cells -- may play a key role in harboring important proteins the cells need for signaling, gene expression and cell division: the Smads.
The link between these Smad proteins and the microtubular system could provide clinicians with important potential targets for new drugs against diseases as diverse as cancer, heart disease and certain inflammatory ailments.
"If we are right, we might be able to design small molecules that would either stabilize or disrupt the interaction between these two critical cellular systems," explained Pascal Goldschmidt, director of Ohio State University's Heart and Lung Institute.
Chunming Dong, lead author and a research scientist in Goldschmidt's laboratory at the Institute, published their findings in the current issue of the journal Molecular Cell.
Discovered more than five years ago, Smad proteins have been found to be key players in the signaling underway within living cells. Some Smad proteins combine to form molecular complexes necessary for initiating gene expression. Others, however, play a role in halting that same process.
The Smad proteins are believed to be the most important regulatory component of the TGF-beta (transforming growth factor-beta) pathway -- a system essential for cellular proliferation, differentiation, development or apoptosis -- programmed cell death
For example, Smad 2 and Smad 3 protein molecules combine and join with Smad 4 proteins in the cell's cytoplasm before migrating into the cell's nucleus to initiate a gene response. Smad 7, however, blocks the activity of TGF-beta. The distribution of these proteins throughout the cell plays a major role in biochemical signaling along the TGF-beta pathway, Goldschmidt said.
The microtubules, on the other hand, form part of the structural framework of the cell. But they also play other important roles - away from cell division, they help position the nucleus within the cell, assist in the migration of organelles inside the cell and can affect the electrical polarity of a cell. During cell division, they orchestrate the splitting of chromosomes between the two daughter cells.
Dong and Goldschmidt's research suggests that when the Smad proteins are sequestered along these microtubules, there is a decrease in the activity along the TGF-beta pathway. When the Smad proteins are released from the microtubules, the TGF-beta pathway activity increases and the protein complexes can interact with their target DNA in the nucleus, initiating a gene response.
The TGF-beta pathway is a key system in biology and illness. It is extremely important in inflammation, in cancer development and heart disease, Goldschmidt said.
"We've shown that if you disrupt the microtubules, the tendency of the Smad proteins to promote gene expression is strongly enhanced," he said. "If you strengthen the microtubules, they then draw in the Smads and the TGF-beta pathway activity is reduced."
The researchers are suggesting that drugs like Taxol, which is effective against ovarian and breast cancer, may work by strengthening the microtubular system, and thereby sequestering more of the Smad proteins, blocking the TGF-beta pathway and subsequent gene expression.
Other drugs like colchicine, which is effective against inflammatory gout, may succeed by destabilizing the microtubules, thereby releasing more Smad proteins and enhancing the TGF-beta pathway.
"We've shown that the functions of the TGF-beta pathway and the microtubular system in cells are strongly interrelated," Goldschmidt said. "If the microtubular system of the cell is changed, the efficacy of the TGF-beta pathway is remarkably affected.
"We're proposing that the mechanism by which certain drugs have been shown to be beneficial against ailments as disparate as cancer, gout and heart disease may be because of their impact on the TGF-beta pathway that is mediated by Smad protein interaction with microtubules."
For Goldschmidt, these findings bring a strange sense of history. A decade ago as a postdoctoral fellow, he discovered a similar situation in a system that links actin filaments and epidermal growth factor effector proteins. That gave him an added advantage in seeing the importance of this latest discovery.
"It is a different pathway from the one 10 years ago but it seems very much like deja vu to me," he said.
The research was supported by grants from the National Institutes of Health, the American Heart Association and the Scleroderma Research Foundation.
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