Disease relevance of MSN2

• The trehalose concentration in the msn2 msn4 double mutant increases less during heat stress and drops more slowly during recovery than in wild-type cells [1].
• MSN2 encodes a Cys2His2 zinc finger protein related to the yeast MIG1 repressor and to mammalian early growth response and Wilms' tumor zinc finger proteins [2].

High impact information on MSN2

• Stress-resistance transcription factors Msn2/Msn4 and protein kinase Rim15 were required for this life-span extension [3].
• Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase [4].
• Apart from PKA, the protein kinase Snf1 can also directly modify one of the Msn2 phosphorylation sites (S582) and thereby repress Msn2 function [5].
• A dual role for PP1 in shaping the Msn2-dependent transcriptional response to glucose starvation [5].
• Msn2 activation by sudden glucose depletion correlates with a fast but transient decrease in phosphorylation of several sites in its nuclear localization signal (NLS) [5].

Biological context of MSN2

• The MSN2 and MSN4 genes encode homologous and functionally redundant Cys2His2 zinc finger proteins [6].
• A disruption of both MSN2 and MSN4 genes results in a higher sensitivity to different stresses, including carbon source starvation, heat shock and severe osmotic and oxidative stresses [6].
• We present evidence that the MSN2 homolog, MSN4, can partially replace MSN2 for transcriptional activation following stress [7].
• Deletion of MSN2/4, encoding transcription factors driving STRE-dependent gene expression, decreased DUR [8].
• Furthermore, heat shock induction of a STRE-driven reporter gene was reduced more than 6-fold in the msn2 strain relative to wild-type cells [7].

Anatomical context of MSN2

• In cells growing in glucose, Msn2 is located mainly in the cytosol, whereas in carbon source-starved cells, Msn2 is located largely inside the nucleus [9].

Associations of MSN2 with chemical compounds

• However, the Msn2/Msn4-independent mechanism exists for heat control of trehalose metabolism [1].
• Overexpression of Msn2 conferred a much greater sensitivity to methylmercury in yeast, while deletion of the corresponding gene lowered the degree of resistance to methylmercury induced by overexpression of Bop3 [10].
• To approximate the effect of low PKA activity on Msn2, we generated a mutant form with alanine substitutions in PKA phosphorylation sites [11].
• Surprisingly, glucose repression of HSP12 appeared to be independent of Msn2/4p: HSP12 transcription in glycerol-grown cells was unaffected in a deltamsn2deltamsn4 strain [12].
• Among the GTO genes, GTO2 shows the strongest induction of expression by agents such as diamide, 1-chloro-2,4-dinitrobenzene, tert-butyl hydroperoxide or cadmium, in a manner that is dependent on transcriptional factors Yap1 and/or Msn2/4 [13].

Physical interactions of MSN2

• Moreover the transactivating region of Msn2 interacts in vitro with the N-terminal domain of Gal11 [14].

Regulatory relationships of MSN2

• HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene [15].
• These genes are activated by Msn2 and repressed by the Srb10 kinase, a member of the mediator complex [16].
• Mutations that decrease the activity of the Ras/Cyr1/PKA pathway also extend longevity and increase stress resistance by activating transcription factors Msn2/Msn4 and the mitochondrial antioxidant enzyme superoxide dismutase (Sod2) [17].
• The localization defect in these mutants is specific for carbon starvation stress, and it is because of the presence of an abnormally active Snf1 protein kinase that inhibits the nuclear localization of Msn2 upon carbon starvation [9].
• Similar effects were found in msn5 mutant cells that block Msn2 nuclear export [11].

Other interactions of MSN2

• Our results suggest that MSN2 and MSN4 encode a DNA-binding component of the stress responsive system and it is likely that they act as positive transcription factors [6].
• However, the contribution of Hsf1, independent of Msn2/4, is only beginning to emerge [18].
• However, we found that reduction or elimination of PKA activity strongly derepresses transcription of the small heat-shock genes HSP26 and HSP12, even in the absence of MSN2/4 [19].
• These results indicate that, in addition to trehalose, Hsp104 and the Msn2/4-controlled genes, other factors exist in S. cerevisiae that can, significantly and independently of the known factors, enhance general stress resistance [20].
• The multicopy suppressors of the snf1 defect, Msn2p and Msn4p transcription factors (Msn2/4p), activate genes through the stress-responsive cis element (CCCCT) in response to various stresses [21].

Analytical, diagnostic and therapeutic context of MSN2

• Disruption of the MSN2 gene abolished an STRE-binding activity in crude extracts as judged by both gel mobility-shift and Southwestern blot experiments, and overexpression of MSN2 intensified this binding activity [7].
• We analyzed the two-dimensional gel electrophoresis pattern of protein synthesis of the msn2 msn4 double mutant and compared it with that of the wild-type strain during exponential growth phase and at the diauxic transition [21].

References