RING Finger proteins target cellular molecules for disposal

June 06, 2002

(Embargoed) CHAPEL HILL - Scientists at the University of North Carolina at Chapel Hill have discovered another facet to the molecular engine that targets cell proteins for elimination.

The discovery was made in Drosophila, fruit flies, which share with mammals the same group of genes that code for proteins involved in regulating this targeting process. A report of the findings appears June 7 in the journal Developmental Cell.

The destruction of proteins during the cycle of cell growth and division is as important as protein production. Depending on when in the cycle it occurs, a breakdown in this proteolysis process can either stop a cell from dividing and replicating its chromosomes, or it can result in cell growth run amok, becoming cancerous. Because of its implications for health and disease, exactly how proteolysis is regulated, how cells "know" which proteins to eliminate and when, is the subject of intense scientific investigation.

"Many proteins that are important regulators of progress through the cell division cycle are inactivated by being destroyed, reduced to their component parts at particular times in the cycle. And that destruction, through ubiquitin-mediated proteolysis, is necessary for cell cycle regulation," said the report's senior author Dr. Robert J. Duronio, associate professor of biology at UNC and a member of the Program in Molecular Biology and Biotechnology at the School of Medicine.

This proteolysis process involves attachment to other proteins of the small protein, ubiquitin. The attachment is a signal for proteolysis; it tells the proteolytic machine to destroy the ubiquitinated protein, to chew it up and decompose it.

"A family of enzymes in cells puts ubiquitin onto the target proteins. And among the most important members of this family are E3 ubiquitin ligases," Duronio said. "These have received a lot of attention because they're thought to be the enzymes that recognize which proteins will get ubiquitinated."

The SCF complex is a variety of E3 ubiquitin ligase. Cells with a mutated or non-functioning SCF will divide when they're not supposed to if particular proteins are not destroyed properly during the cell cycle phase in which the decision to proliferate is made. Essentially, these cells now contain "a chronic 'go' signal," said Duronio, "which gives them a growth advantage, one of the requirements for tumor development."

According to Duronio, the SCF complex contains many components, one of which was thought to mediate recognition of 'go signal' proteins by E3 ubiquitin ligase.

Now it appears that recognition of such proteins is also mediated by another SCF component comprised of RING Finger proteins. Though similar in amino acid sequence, they are functionally distinct. Each of the three proteins studied contributes differently to the ability of the SCF complex to recognize protein targets that are to be ubiquitinated and proteolyzed.

Apart from studies in yeast cells, "this is the first time anyone has genetically analyzed this particular component of the SCF complex in an animal setting," Duronio said.

Mammalian cells also have this SCF component, thus raising the possibility that different RING finger proteins will be involved in different cellular processes that might be involved in the development of cancer.
Along with Duronio, biology dept. co-authors are Maher A. Noureddine and Stephen A. Thacker. Timothy D. Donaldson is with UNC Lineberger Comprehensive Cancer Center.

Funding for the research came from the National Institute of General Medicine, National Institutes of Health.

Note: Contact Duronio at 919-962-7749, duronio@med.unc.edu

School of Medicine contact, Les Lang, 919-843-9687, llang@med.unc.edu

UNC School of Medicine

University of North Carolina Health Care

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