SUMMARY PARAGRAPH for MSN4
MSN2 and MSN4 encode transcription factors that regulate the general stress response of S. cerevisiae (2, 5). Msn2p and Msn4p regulate the expression of ~200 genes in response to several stresses, including heat shock, osmotic shock, oxidative stress, low pH, glucose starvation, sorbic acid and high ethanol concentrations, by binding to the STRE element, 5'-CCCCT-3', located in the promoters of these genes (2, 6, 7). MSN4 gene expression is itself Msn2/4p dependent and induced by stress, while MSN2 expression is constitutive (6).
Msn2p and Msn4p are largely, but not completely, functionally redundant and there is increasing evidence that the individual regulatory contributions of these transcription factors differ for specific genes and under particular stress conditions (reviewed in 8). The two proteins share 41% identity and are similar in size and amino acid composition (1). While single deletion mutants of msn2 and msn4 have no obvious phenotype, msn2msn4 double null mutants are hypersensitive to carbon source starvation, heat shock, and osmotic and oxidative stresses and overexpression of MSN2 and MSN4 genes decreases sensitivity to starvation and thermal stresses (1 and reviewed in 8).
In their N-terminal halves, Msn2/4p contain transcription-activating domains and a nuclear export sequence (9, 10). At the C-terminus, both proteins contain a zinc-finger binding domain that recognizes the STRE element (2, 5). DNA binding by Msn2p is thought to be regulated by stress and by the kinases cAMP-dependent protein kinase (PKA, composed of Tpk1p, Tpk2p, and Tpk3p and regulatory subunit Bcy1p) and Gsk3p (3, 11). Adjacent to the zinc-finger, Msn2p and Msn4p each contain a nuclear localization signal, which is inhibited by PKA phosphorylation and activated by protein phosphatase 1 dephosphorylation (10, 3, 12).
Under non-stress conditions, Msn2p and Msn4p are located in the cytoplasm (3). Cytoplasmic localization is partially regulated by TOR signalling with the 14-3-3 protein Bmh2p acting as a cytoplasmic anchoring partner for Msn2/4p (13). Upon stress, Msn2/4p are hyperphosphorylated, relocalized to the nucleus and then display a periodic nucleocytoplasmic shuttling behavior (3, 14, 15). Nuclear export of Msn2p has been shown to be dependent on the exportin Msn5p and nuclear localization at both the import and export level is regulated by PKA (3, 10, 15). Msn2p is also positively regulated by the Psr1p/Whi2p phosphatase complex and negatively regulated by Snf1p phosphorylation and by its degradation in the nucleus, a process dependent on the cyclin-dependent kinase Ssn3p (16, 12, 17).
Genes similar to MSN2/4 have been identified in Schizosaccharomyces pombe, Trichoderma atroviride, and Candida albicans (18, 19, 20). However, the C. albicans Msn2- and Msn4-like proteins do not appear to play a significant role in the stress response of this fungal pathogen (20).
Last updated: 2007-01-17