Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells

Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. SMCs are not terminally differentiated and possess the ability to modulate their phenotype in response to changing local environmental cues. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMC with particular focus on examination of processes that contribute to the repression of SMC marker genes. We discuss the environmental cues which actively regulate SMC phenotypic switching, such as platelet-derived growth factor-BB, as well as several important regulatory mechanisms required for suppressing expression of SMC-specific/selective marker genes in vivo, including those dependent on conserved G/C-repressive elements, and/or highly conserved degenerate CArG elements found in the promoters of many of these marker genes. Finally, we present evidence indicating that SMC phenotypic switching involves multiple active repressor pathways, including Krüppel-like zinc finger type 4, HERP, and ERK-dependent phosphorylation of Elk-1 that act in a complementary fashion.

Mutant tryptophan aporepressors with altered specificities of corepressor recognition.

The Escherichia coli trpR gene encodes tryptophan aporepressor, which binds the corepressor ligand, L-tryptophan, to form an active repressor complex. The side chain of residue valine 58 of Trp aporepressor sits at the bottom of the corepressor (L-tryptophan) binding pocket. Mutant trpR genes encoding changes of Val58 to the other 19 naturally occurring amino acids were made. Each of the mutant proteins requires a higher intracellular concentration of tryptophan for activation of DNA binding than wild-type aporepressor. Whereas wild-type aporepressor is activated better by 5-methyltryptophan (5-MT) than by tryptophan, Ile58 and other mutant aporepressors prefer tryptophan to 5-MT as corepressor, and Ala58 and Gly58 prefer 5-MT much more strongly than wild-type aporepressor in vivo. These mutant aporepressors are the first examples of DNA-binding proteins with altered specificities of cofactor recognition.

The lactose system inKlebsiella aerogenesV9A: 4. A comparison of thelacoperons ofKlebsiellaandEscherichia coli

SUMMARYKlebsiella aerogenesV9A contains twolacoperons, one chromosomal and one borne by the Lac plasmid,FKlac. It is shown that the plasmid Lac repressor resembles that ofEsherichia coliin that it represses theE. colioperon but is inactivated by melibiose. In contrast, the chromosomal Lac repressor of V9A is unable to repress theE. colioperon or the FKlacoperon, but is converted into an active repressor of both these operons on becoming bound to melibiose. The chromosomal Lac repressor is able to repress its own operon whether or not it is bound to melibiose, but is inactivated by isopropyl-β-D-thiogalactoside. These results support the hypothesis that theKlebsiellaLac plasmid was derived from an ancestralE. colichromosome.