Hot Papers

M.J. Birnbaum, Identification of a novel gene encoding an insulin-responsive glucose transporter protein, Cell, 57:305-15, 21 April 1989. Morris J. Birnbaum (Harvard Medical School, Boston): Almost 10 years prior to the publication of this paper, other researchers formulated a model to explain the rapid and reversible insulin-stimulated increase in glucose uptake in responsive target tissues: the hormone effects the redistribution of hexose transporter proteins from a latent intracellular compartment to the plasma membrane (S.W. Cushman and L.J. Wardzala, J. Biol. Chem., 255:4758-62, 1980; and K. Suzuki and T. Kono, Proceedings of the National Academy of Sciences, USA, 77:2542-5, 1980). Since that time, there has been a striking lack of correlation between estimates of transporter translocation and measurements of increased transport. One possible explanation for this discrepancy was the existence of another glucose transporter expressed in insulin-responsive tissues and not recognized by the then-available antibody probes. This paper, as well as others published simultaneously by independent investigators, describes the molecular cloning of a cDNA encoding such a putative `insulin- responsive' hexose carrier. The demonstration of its existence suggests a previously unrecognized complexity in the hormonal regulation of peripheral metabolism. It also raises the question as to whether this newly discovered transporter could be a site of abnormality causally linked to the development or maintenance of insulin-resistant diabetes mellitus. M.J. Berridge, R.F. Irvine, Inositol phosphate and cell signalling, Nature, 341, 197-205, 21 September 1989. Michael Berridge (University of Cambridge, England): Five years ago we published a review (Nature, 312:315-21, 1984) that became one of the 10 most cited papers of the decade (The Scientist, Jan. 8, 1990, page 18). This earlier review described the discovery of the novel second messenger inositol trisphosphate (IP3). Our 1989 review is beginning to have a similarly large impact because it not only summarizes the metabolic relationships between the ever- expanding family of inositol phosphates, but also explores emer- ging concepts concerning the dynamic aspects of calcium signaling. When cells are stimulated, they invariably display regular calcium oscillations. The individual spikes that make up such oscillations often have a discrete spatial organization in that they initiate at a fixed point and then spread through the cell as a calcium wave. We have presented a model that attempts to explain how IP3 functions to set up these wave-like calcium transients. We suspect our review has become popular because it presaged the importance of these spatiotemporal aspects, which are now providing such new and exciting insights into calcium signaling. ALEPH Collaboration, D. DeCamp, et al., Determination of the number of light neutrino species, Physics Letters B, 231, 519-29, 16 November 1989. Jacques Lefran!ois (European Organization for Nuclear Research [CERN], Geneva, Switzerland): Our paper is based on the measurement of the first 3,000 events that were collected by the ALEPH Collaboration [named after one of the detectors] at the start-up of the large e+-e- collider (LEP) at CERN. At the energy at which LEP is operating, the electron positron annihilation creates a Z0 boson in more than 99 percent of the cases. The Z0 then decays in all elementary particle-antiparticle pairs whose masses are low enough. From this first accurate measurement of the Z0 mass, width, and decay branching ratios, the probability of the Z0 to decay in neutrino pairs (which are invisible in the apparatus) can be determined. This probability is proportional to the number of neutrino species whose number was known to be less than five at the moment. Our measurement established the number of neutrino species to be exactly three corresponding to the already known fermion families. This decisive determination of the number of fermion families has important implications for the theory of elementary particles. It also has a large impact on cosmology, since the number of neutrino species had a major influence in nucleosynthesis at the time of the Big Bang, and extra neutrino species had been postulated as candidates for the missing mass of the universe. J. Meisenhelder, P.-G. Suh, S.G. Rhee, T. Hunter, "Phospholipase C-g is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro," Cell, 57, 1109-22, 30 June 1989. Jill Meisenhelder (Salk Institute, San Diego): Although it had long been appreciated that growth factor treatment stimulates phosphatidylinositol (PI) turnover in certain cells, this paper was one of several that began to define the molecular link between these two events. We found that PDGF and EGF treatments cause rapid and extensive phosphorylation of the PLC-g isoform of phospholipase C on tyrosine concomitantly with increased PI turnover. This finding, when taken together with our observation that purified growth factor receptor protein-tyrosine kinases can phosphorylate the identical tyrosine residues in vitro, strongly suggested that PLC-g is activated by tyrosine phosphorylation. Subsequently, by using phosphorylation site mutants and overexpression of PLC-g, other groups have shown that this is indeed the case. Previously, it was thought that PLCs are activated via G proteins; the direct phosphorylation of a PLC by protein-tyrosine kinase receptors thus suggested a novel mechanism of activation for this class of enzyme. S.T. Smale, D. Baltimore, The `initiator' as a transcription control element, Cell, 57, 103-13, 7 April 1989. Stephen T. Smale (University of California, Los Angeles): For several years, the TATA box has been studied extensively as the central mediator of eukaryotic transcription initiation. However, numerous studies suggested that not all promoters contained TATA elements. Our paper extended those studies by identifying and characterizing a discrete sequence element at the start site of the `TATA-less' terminal transferase gene that functionally replaces TATA both in vivo and in vitro. Promoter constructs containing either this initiator element or a TATA element can now be studied biochemically to compare their mechanisms of transcription initiation. These studies are facilitated by the recent and exceedingly important isolation of genes encoding general transcription factors, most notably the gene for TFIID. Interestingly, we and others have found that TFIID, which binds to TATA boxes, is required for both TATA- and initiator-mediated transcription. A.W. Murray, M.W. Kirschner, "Cyclin synthesis drives the early embryonic cell cycle," Nature, 339, 275-80, 25 May 1989. A.W. Murray, M.J. Solomon, M.W. Kirschner, "The role of cyclin synthesis and degradation in the control of maturation promoting factor activity," Nature, 339, 280-6, 25 May 1989. A.W. Murray, M.W. Kirschner, "Dominoes and clocks: the union of two views of the cell cycle," Science, 246, 614-21,3 November 1989. Andrew Murray (University of California, San Francisco): The two Nature papers describe the use of extracts of frog eggs to study the role of the protein cyclin in inducing mitosis. We developed and characterized egg extracts that perform multiple cell cycles in vitro. These extracts are proving to be extremely useful in studies of the regulation of the cell cycle and the mechanism of mitosis. Cyclin was originally identified by Tim Hunt of the University of Cambridge and his colleagues as a protein that accumulates during interphase and is destroyed at the end of each mitosis (Cell, 33:389-96, 1983). It has long been known that protein synthesis is required for the induction of mitosis. In conditions in which cyclin is the only protein being synthesized, the cell cycle continues, and the rate of the cell cycle increases with the rate of cyclin synthesis. This experiment shows that, among newly synthesized proteins, cyclin is sufficient to induce mitosis and that cyclin must accumulate to a critical threshold in order to induce mitosis. We also demonstrated that cyclin degradation is required for the exit from mitosis, suggesting that physiological controls over the exit from mitosis may work by controlling the stability of cyclin. The review paper in Science describes recent advances in cell cycle research and how they have led to a unified view of how the cell cycle works in all eukaryotes. The basic conclusions are: 1) cell cycle events are induced by changes in the activity of a protein kinase complex composed of the cdc2 protein and cyclin; 2) the components of this complex and the proteins that regulate its activity have been highly conserved during evolution; 3) in spite of this functional conservation, the component whose accumulation is rate limiting for the induction of mitosis is different in different cell cycles.

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