Interferon interferes with vital viral, tumorigenic and inflammatoryprocesses _ but what interferes with interferon?
When one of those pathogenic challenges to a cell's well-beingactivates expression of the interferon gene, it in turn turns on STAT_ signal transducers and activators of transcription _ in the cell'scytoplasm. STAT then makes its way to the cell's nucleus, where itbecomes a target for degradation by a feedback mechanism called theubiquitin-proteosome pathway.
"It was previously thought," Harvard University molecular biologistTom Maniatis told BioWorld Today, "that this pathway degraded,misfolded or damaged proteins, and so on. When cytokines, in thiscase interferon, interact with a cell," he explained, "they induce awhole cascade of signaling events, in this case STAT, that leads toactivation of different genes."
He continued: "When you activate these transcription factors, it'simportant that they are not continuously in the `on' position. Becauseif they were, this whole cascade would continue to go, and amplifyout of control.
"The best way to look at it," Maniatis said, "is that continualexpression of the cytokine pathways is toxic. So a continual treatmentof interferon or other cytokines will kill cells."
To keep this from happening, cells make sure that STAT activation isself-limiting. "The question has been," Maniatis continued, "Whatcontrols its transient activation?"
He gives one answer to this question in the current issue of Science,dated Sept. 20, 1996, in an article titled: "Regulation of interferon-g-activated STAT1 by the ubiquitin-proteosome pathway."
"What this paper shows," Maniatis said, "is that when interferon-gamma binds to a membrane-bound receptor, it activates the STAT1,which translocates to the nucleus and becomes a target fordegradation by the ubiquitin-proteosome pathway."
Ubiquitin, as its name implies, occurs in virtually all mammaliancells. "Ordinarily, when a large number of proteins are marked forbreakdown in cells," Maniatis said, "a whole cascade of enzymesattaches a short _ 76-amino-acid _ peptide, ubiquitin, to lysineresidues on the target proteins."
Thus flagged for degradation, the protein can be recognized by a veryhigh molecular weight enzyme complex, the proteosome.
Besides this ubiquitin-proteosome pathway to curtailing STATactivation, Maniatis pointed out, a second route to protein destructionis about to be published by James Darnell, of Rockefeller University:"He shows that when the phosphorylated cytokine goes into the cell'snucleus, a phosphatase dephosphorylates it, and it then exits thenucleus.
"In inflammatory diseases," Maniatis said, "a major question is howcytokines are transiently regulated. And these two processes _nuclear degradation and nuclear export _ point to one specificmechanism, the ubiquitin-proteosome pathway."
ProScript Inc., of Cambridge, Mass., a start-up research anddevelopment company that Maniatis co-founded in 1992, is dedicatedto pathfinding that pathway.
The firm's executive director of research and development, JulianAdams, told BioWorld Today: "Tom's paper in Science certainlygives us food for thought. It's something that was actuallyunexpected, and shows that the molecular biology of the cell is ever-more complicated, with as-yet-unexplored targets out there."
ProScript's target is inhibiting proteosome in such areas asinflammation and cancer. It has a research partnership with HoechstMarion Roussel in Kansas City, Mo., a subsidiary of Hoechst AG inFrankfurt am Main, Germany. (See BioWorld Today, Nov., 10, 1995,p. 1.)
"We are still in the preclinical stage of this collaboration," Adamssaid, "and continuing to make progress. We have a variety of animalstudies completed and ongoing in arthritis, asthma, and murine andhuman cancers."
ProScript's candidate therapeutic inhibitor, he added, "is a small,orally available molecule that inhibits proteosome."
Maniatis, who also co-founded Genetics Institute Inc., of Cambridge,Mass., sits on the boards and scientific advisory boards of bothcompanies. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.