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T.D. Halazonetis, K. Georgopoulos, M.E. Greenberg, P. Leder, "c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities," Cell, 55, 917-24, 2 December 1988. Thanos Halazonetis (Harvard Medical School, Boston): "A number of cancer-causing genes (oncogenes) have been shown to code for factors regulating gene expression. The protein products of two such oncogenes, c-jun and c-fos, had been shown to be part of a protein complex that regulates the transcription of genes associated with cell division and differentiation. In this paper, we describe how the interaction of the Jun and Fos proteins modulates their DNA-binding activity. When the Jun and Fos proteins are cotranslated, they form a heterodimer of high specific DNA-binding activity. The two proteins have homologous domains that mediate heterodimer formation and subsequent DNA binding. The domain of the Jun protein, in addition to interacting with the homologous domain of the Fos protein, can also interact with itself, so that Jun protein translated in the absence of Fos forms a homodimer with DNA-binding activity of the same specificity as that of the Jun/Fos heterodimer, but of lower affinity. "The requirement for heterodimer formation to achieve high affinity DNA-binding activity may provide a more stringent control of the transcription of genes involved in cell division. This control, however, might be overcome by over-expression of one of the members of the heterodimer - in this case, Jun - leading to uncontrolled cellular proliferation." B.A. Larder, G. Darby, D.D. Richman, "HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy," Science, 243, 1731-34, 31 March 1989. Brendan Larder (The Wellcome Research Laboratories, Kent, England): "Zidovudine is the only drug currently approved for the treatment of AIDS and AIDS-related complex (ARC). Its introduction was a significant breakthrough in the fight to control human immuno- deficiency virus (HIV) infection, although it was accepted that zidovudine was not a `cure' for AIDS. It is unclear why the clinical benefits of zidovudine are not sustained in all patients; but one possibility was the emergence of HIV variants resistant to the drug. Results of the first extensive investigation of HIV sensitivity during zidovudine therapy were reported in this paper. "HIV was isolated from individuals with AIDS or ARC before and during zidovudine treatment and tested for sensitivity to the drug. The virus was uniformly sensitive during the first six months of treatment, whereas at later times most isolates showed some evidence of reduced sensitivity. Very significant levels of resistance were observed in viruses isolated from five out of 15 individuals treated for nine months or more. This high incidence was unexpected and raised questions concerning the clinical relevance of these observations. In addition, significant interest was generated in the potential use of combination therapy to help prevent resistance." M. Kozak, "The scanning model for translation: an update," The Journal of Cell Biology, 108, 229-41, February 1989. Marilyn Kozak (University of Pittsburgh, Pa.): "I think the value of this paper lies in its perspective. Written 10 years after the scanning model was proposed, the paper summarizes a wealth of evidence in support of the model. The updated rules for recognition of AUG initiator codons by eukaryotic ribosomes seem to be useful in predicting the pattern of translation from cloned genes and in designing expression vectors. "Some experiments that purport to contradict the scanning model have been cited extensively in the literature, and this review provided an opportunity for me to explain the weaknesses in many of those experiments. These clarifications in turn focus attention of the (remarkably few) mRNAs whose translation really cannot be explained by straightforward application of the existing rules."

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