The age-old appeal to avoid 'shooting the messenger' is apparently left unheeded by the body's protein regulation system. Researchers at the Weizmann Institute of Science have recently uncovered one of the mechanisms underlying the synthesis and regulation of actin - the most abundant protein in eukaryotic cells. Their findings reveal an intricate autoregulatory system based on destroying actin's messenger RNA.
Actin serves as the central building block of microfilaments - the cytoskeletal fiber system influencing cell shape, division, adhesion, and motility. In turn, these cellular functions control important biological processes, including embryonic development and wound healing. In order to perform these diverse functions effectively, actin levels need to be balanced with clockwork precision. Indeed, faulty actin regulation can have wide-ranging, often devastating effects, including the onset of cancer and blood diseases.
Professor Avri Ben-Ze'ev, together with Prof. Alexander Bershadsky and doctoral student Anna Lyubimova of the Weizmann Institute's Department of Molecular Cell Biology have recently zeroed in on one of the actin regulatory mechanisms. Their findings, published in the November, 1999 issue of the Journal of Cellular Biochemistry, further the understanding of a central question in biology, namely, the interplay between cell shape and structure, and gene expression.
Actin exists in the cell in two states: a monomeric (or single unit) form, and a polymeric state (consisting of a chain of monomeric units). In a previous study, the researchers found that actin synthesis is regulated by the fine balance between these two forms. When in excess, the monomeric actin 'shuts off' its own synthesis by destroying the machinery necessary for its production. It exerts a negative feedback mechanism leading to the degradation of its messenger RNA (which carries the genetic instructions required for its biosynthesis). The researchers unraveled this mechanism by introducing natural substances known to modify the polymeric - monomeric actin balance. These included latrunculin A, derived from a Red Sea sponge (which in nature serves as a potent defense mechanism, exerting a lethal anti-predatory effect by causing actin depolymerization).
Yet how does the monomeric actin monitor and regulate its own levels? Prof. Ben-Ze'ev and his team used a dual intervention strategy in order to pinpoint the precise 'sensor' responsible. They increased the monomeric actin levels (using latrunculin), together with systematically deleting minute parts of the actin encoding mRNA. Their reasoning? They hoped to find which part of the actin gene, when deleted, would prevent the negative feedback system from kicking in.
The researchers found that this form of actin regulation depends on sequences localized in the actin mRNA 3'untranslated region (3'-UTR). 'This region contains a 'zip code' binding site, which apparently triggers actin mRNA degradation when, due to excess monomeric actin levels, actin mRNA overflows into 'unacceptable' parts of the cell,' Ben-Ze'ev explains. Deleting this region led to a dramatic increase in monomeric actin levels, coupled with severe aberrations in cell morphology and the structure of the actin cytoskeleton.
The Weizmann team's discovery of a direct link between regulating the genetic expression of actin mRNA and specific changes in cytoskeletal dynamics, represents a breakthrough in understanding the relationship between gene expression and cell morphogenesis at the molecular level.
This study was funded by the Minerva Foundation, the Israel Ministry of Science, and the German-Israeli Foundation for Scientific Research and Development. The generous support of the Yad Abraham Center for Cancer Diagnostics is also acknowledged.
Prof. Avri Ben-Ze'ev holds the Lunenfeld-Kunin Professorial Chair in Genetics and Cell Biology.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.