Figure 1

Regulation of the ubiquitin ligase SCF^Met30 and its connection to cell cycle control. SCF^Met30 ubiquitinates the transcriptional activator Met4 on lysine 163 to maintain it in an inactive state. Degradation of poly-ubiquitinated Met4 is prevented by an ubiquitin-interacting motif (UIM) in Met4. The sulfur containing compounds methionine, cysteine, and S-adenosylmethionine stimulate Met4 ubiquitination, but when their intracellular concentrations are low, reduced ubiquitination combined with Met4 deubiquitination by a so far unidentified deubiquitinating enzyme(s) (Ubp) leads to Met4 activation. Cadmium and arsenic stress inhibit Met4 ubiquitination by inactivation of the ubiquitin ligase SCF^Met30. The resulting activation of Met4 raises cellular glutathione levels due to induced expression of Gsh1. Active Met4 induces expression of a number of genes involved in the sulfur amino acid synthesis pathway (MET-genes) as well as GSH1. MET-gene expression depends on either one of the two homologous zinc-finger proteins Met31 and Met32. Met4 activation also inhibits a number of cell cycle events and can lead to cell cycle arrest. The Met4-dependent cell cycle arrest requires Met32 but cannot be mediated by Met31.