Imagine receiving only negative input, never any encouragement. In the mid-1960s, after Jacob and Monod's findings earlier that decade, negative (repressor) control was the only known system of regulation for the transfer of information encoded by DNA to newly synthesized enzyme molecules. However, this was about to change.
Despite the distractions of the 'swinging' 1960s, scientists still managed to find time to study operons in Escherichia coli. A hint that positive regulation occurred came from Englesberg and colleagues, who concentrated on the three genes of the ara operon (araA, araB and araD) that encode inducible enzymes required for use of the sugar arabinose, along with a fourth gene (araC) that they found to encode the regulator.
araC− mutants were known to be deficient for all three enzymes and a permease. Englesberg and co-workers, however, isolated araCc mutants, which were constitutive for these components. In complementation experiments, the araCc mutants were dominant to the araC− mutants. Because araC is separate and distinct from araA, araB and araD, the authors postulated that the araC gene had an 'activator' function — araC+ (wild type) plus the inducer L-arabinose, or araCc without L-arabinose, produce a factor required for expression of the ara operon.
This concept of 'positive control' by 'activators' received a cold response from Jacob and Monod. However, 5 years later, in 1970, Beckwith and colleagues, and Pastan, Emmer and co-workers resolved the matter when both groups characterized an activator of the lac operon. Expression of the lac operon is inhibited in the presence of glucose and its catabolites, and increased levels of cyclic AMP (cAMP) had shortly before been shown to reverse the inhibitory effect of glucose and its catabolites. Beckwith and colleagues proposed that cAMP binds to a protein factor, the catabolite gene-activator protein (CAP), causing it to bind to a DNA site in the lac promoter and stimulate transcription initiation. Using the first cell-free system for transcription and translation, they showed directly that CAP plus cAMP stimulated the expression of the lac operon. Emmer et al. isolated and characterized the same factor based on assays of cAMP binding activity and named it cAMP receptor (CR) protein (later revised to CRP). The intricacies of how CAP plus cAMP binding promotes RNA polymerase activity are now understood in considerable detail. Something 'positive' definitely emerged from these studies.
References
ORIGINAL RESEARCH PAPERS
Englesberg, E., Irr, J., Power, J. & Lee, N. Positive control of enzyme synthesis by gene C in the L-arabinose system. J. Bacteriol. 90, 946–957 (1965)
Zubay, G., Schwartz, D. & Beckwith, J. Mechanism of activation of catabolite-sensitive genes: a positive control system. Proc. Natl Acad. Sci. USA 66, 104–111 (1970)
Emmer, M., deCrombrugghe, B., Pastan, I. & Perlman, R. Cyclic AMP receptor protein of E. coli: its role in the synthesis of inducible enzymes. Proc. Natl Acad. Sci. USA 66, 480–487 (1970)
FURTHER READING
Sheppard, D. & Englesberg, E. Further evidence for positive control of the L-arabinose system by gene araC . J. Mol. Biol. 25, 443–454 (1967)
Varmus, H., Perlman, R. & Pastan, I. Regulation of lac transcription in Escherichia coli by cyclic adenosine 3′,5′-monophosphate. J. Biol. Chem. 245, 6366–6372 (1970)
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Bussell, K. Accentuate the positive. Nat Rev Mol Cell Biol 6 (Suppl 1), S7 (2005). https://doi.org/10.1038/nrm1793
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DOI: https://doi.org/10.1038/nrm1793
