Findings On Cell Communication May Help Fight Three Genetic Diseases

Alan M. Tartakoff, professor of pathology and director of the Cell Biology Program, and Jayasri Nanduri, assistant professor in the Institute of Pathology, made some remarkable observations that appear in the August issue (published August 31) of Molecular Cell, a highly respected journal in cell/molecular biology. Their article is entitled "The Arrest of Secretion Response in Yeast: Signaling From the Secretory Path to the Nucleus, via Wsc Proteins and Pkclp."

Their study found unexpected coordination of cellular activities -- whether or not a cell can secrete proteins will profoundly regulate the transfer of genetic information from the nucleus to the cytoplasm and the structure of its nucleus.

This is important because it was previously thought that the secretory activity of cells was relatively unrelated to gene expression, which is key for controlling the growth of normal and cancer cells. The research also is important because the structural plasticity of the nucleus was not previously appreciated, and because these structural changes provide an opportunity to investigate how the cell nucleus normally maintains its characteristic structure and activities.

In a broader sense, this study provides a context in which to analyze several genetic diseases already being studied in Tartakoff's laboratory -- cystic fibrosis, Huntington's disease, and the fragile X syndrome.

Cells have two distinct compartments -- the nucleus, which houses genes, and the cytoplasm, which executes tasks assigned by the nucleus. Most components found in the nucleus are essentially absent from the cytoplasm -- and vice versa -- and many metabolic functions occur only in the nucleus or only in the cytoplasm.

One of those functions is protein secretion, which carries newly created proteins along the "secretory path" to the cell surface and releases some of those proteins to the surrounding medium. Although the communication, or link, between the nucleus and cytoplasm is not well understood, without it cellular life would be dangerously chaotic.

Tartakoff and Nanduri's research shows that the activity of the secretory path is closely tied to the structure and functions of the nucleus. In particular, when "membrane traffic" along the secretory path is interrupted, import of proteins into the nucleus is largely inhibited, and many proteins normally found in the nucleus relocate reversibly to the cytoplasm.

These changes, referred to as the "arrest of secretion response," are initiated by a family of transmembrane proteins (Wsc proteins) and protein kinase C (Pkc1p). Nanduri's present goal is to understand how Wsc proteins initiate signaling from the secretory path to the nucleus and how the several steps of this signaling are achieved.

Tartakoff said their observations show that the organization of the nucleus is easily influenced by previously unanticipated factors. These findings may impact the future of research on three genetic diseases -- cystic fibrosis, Huntington's disease, and the fragile X syndrome. This is because, in each case, either the secretory path malfunctions or key proteins move between the nucleus and cytoplasm.

Cystic fibrosis is a disease of protein transport along the secretory path. A single gene is mutated, and the corresponding cell surface protein normally regulates cellular chloride content, especially in the lungs. In most affected individuals, this protein is made and accumulates along the secretory path without arriving at the cell's surface. Therefore, identification of genes or drugs that assist the transport of this mutant to the cell surface have become key goals for molecular therapy.

Huntington's disease is a disease of nucleocytoplasmic transport. In this neurodegenerative disease, a single gene is mutated and the corresponding protein, huntingtin, accumulates in the nucleus rather than remaining in the cytoplasm. To understand why this happens, it is necessary to understand what factors normally control protein transport between the nucleus and cytoplasm.

The fragile X (FX) syndrome appears also to be a disease of nucleocytoplasmic transport. FX is the most frequent inherited cause of mental retardation and autism. One protein is missing, and this protein, which binds ribonucleic acid (RNA), can reside in either the nucleus or cytoplasm. It is thought to move repeatedly between the nucleus and cytoplasm and may convey critical messages as it does so. As in Huntington's disease, it is therefore essential to understand how its transport is normally controlled.

The researchers' observations that communication between a cell's nucleus and cytoplasm is subject to previously unknown controls opens unanticipated avenues for investigation of molecular therapies for each of these diseases. There also are indications that many aspects of gene expression and the regulation of cell growth are critically dependent on transport between the nucleus and cytoplasm.