Did You Ever Wonder What Makes a Normal Cell Turn Cancerous?

Rough Sledding for Epithelial Cells

Scientists had long suspected that two closely-related proteins, "Ski" and "Sno," were major contributors to the development of a number of cancers, but their precise role remained a mystery until cell biologist Kunxin Luo and her research group cracked the case. In studying the signaling mechanism of an extracellular protein called TGF-ß (transforming growth factor-beta), they found that Ski and Sno proteins interact with a family of tumor suppressor proteins called "Smad" to completely shut down the TGF-ß signal.

To send a message to a cell's DNA, TGF-ß proteins dock with receptors in the cell's outer membrane, triggering the release of a chemical signal that is picked up by Smad proteins in the cytoplasm and transported into the nucleus. The TGF-ß message can be blocked by abnormally high levels of Sno or Ski proteins, a problem that can result in the cell becoming cancerous.

"Ski and Sno block the downstream events initiated by TGF-ß," Luo says. "Although the way in which Ski interacts with Smad proteins to control TGF-ß signals continues to be a mystery, the mechanism behind the effects of Sno proteins is a negative feedback loop." TGF-ß signals activate genes that, among other things, instruct an epithelial cell to stop growing. If something goes awry, causing the TGF-ß signal to be blocked, cell growth can continue unchecked, giving rise to cancerous tumors. Since the TGF-ß proteins cannot themselves enter a living cell, they transmit their signals by attaching themselves to receptor proteins on a cell's outer surface. The signal generated by this interaction is then ferried across the cell membrane, through the cytoplasm and into the nucleus via Smad proteins. The normal level of Sno proteins inside the nucleus blunts TGF-ß signals, but as the number of Smad proteins increases, the level of Sno drops until it is low enough for the signals to take effect.

"After two hours, the TGF-ß signals have resulted in a marked increase in the expression of the Sno gene," says Luo. "The level of Sno rises until there's enough to block the functions of Smad. This allows a cell to resume normal growth activity."

Luo's research has implications beyond carcinogenesis. In addition to stopping the growth of epithelial cells, TGF-ß signals promote the growth of fibroblast cells and the differentiation of other types of cells, especially muscle cells.

"The discovery of Ski and Sno may lead to their applications in the treatment of fibrosis diseases or in the healing of wounds and the repair of damaged tissue," says Luo.


More about Sno and Ski

 

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Ernest Orlando Lawrence Berkeley National Laboratory