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Abstract

Ubiquitination regulates a host of cellular processes and is well known for its role in progression through the cell division cycle. In budding yeast, cadmium and arsenic stress, the availability of sulfur containing amino acids, and the intracellular concentration of S-adenosylmethionine are linked to cell cycle regulation through the ubiquitin ligase SCF Met30 . Regulation is achieved by ubiquitination of the transcription factor Met4. Met4 activity is controlled by a regulatory K48-linked ubiquitin chain that is synthesized by Cdc34/SCF Met30 . A ubiquitin-interacting-motif (UIM) present in Met4 prevents degradation of ubiquitinated Met4 allowing the ubiquitin chain to function as a reversible switch of Met4 activity. Here we discuss mechanisms of Met4 and SCF Met30 regulation in response to intracellular and environmental conditions, and describe the integration of these signals with cell cycle control.

Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells

“…In the model system, yeast, a regulatory pathway connecting sulfur-containing metabolites, most notably methionine, with cell cycle regulation, has been suggested to respond primarily to S-adenosylmethionine (SAM) levels. [18][19][20] Furthermore, earlier studies showed that reducing SAM synthesis blocks proliferation of leukemic cells. 16,17 Therefore, we hypothesized that methionine dependence is a reflection of limiting SAM availability caused by reduced flux through the methionine metabolic pathway in Met-Hcy+ conditions.…”

“…Lowering the plasma methionine level concomitant with homocysteine supplementation in animal models causes regression of tumors, inhibition of metastasis and blocks growth of solid tumors and leukemia, but has no harmful effects on normal tissues. [12][13][14] The apparent hunger of cancer for methionine is also exploited by clinicians in tumor detection using 11 C-methionine as an alternative tracer for the glucose analog 18 F-FDG in positron emission tomography. 15 Molecular mechanisms describing how methionine dependency induces cell cycle arrest and apoptosis are unknown; however, the diverse ways in which a cell uses methionine are well-understood.…”

“…1D). Because a cell cycle checkpoint monitoring SAM concentrations has been described in yeast, 18,19 it is tempting to speculate that a similar SAM-checkpoint blocks proliferation of cancer cells.…”

A Dominant Suppressor Mutation of the met30 Cell Cycle Defect Suggests Regulation of the Saccharomyces cerevisiae Met4-Cbf1 Transcription Complex by Met32

“…Central to this pathway is the regulation of transcription factor complexes containing the transactivating factor Met4 (2). Met4 regulation is also critical for the cellular response to cadmium and arsenic stress (3)(4)(5)(6)(7). Active Met4 induces expression of a group of genes, commonly referred to as MET genes, that are involved in sulfur assimilation and synthesis of sulfur-containing amino acids (1).…”

“…In addition, Met4 promotes synthesis of the tripeptide glutathione for detoxification under cadmium and arsenic stress conditions by inducing GSH1 expression, a gene that encodes for ␥-glutamyl cysteine synthase, the rate-limiting enzyme in glutathione synthesis (4 -6, 8). Met4 regulation links these metabolic responses to regulation of cell proliferation, because activation of Met4 can induce a complex cell cycle arrest that involves down-regulation of G 1 and S phase cyclin expression, destabilization of prereplication complexes, a block of metaphase to anaphase transition, and reduction in translation (3,5,9,10).…”