MSI1 suppresses hyperactive RAS via the cAMP-dependent protein kinase and independently of chromatin assembly factor-1.
RAS hyperactivation in the yeast Saccharomyces cerevisiae leads to multiple nutritional growth defects associated with overstimulation of the cAMP signaling pathway. Hyperactive RAS can be suppressed by overexpression of MSI1, a subunit of chromatin assembly factor-1 (yCAF-1). MSI1 overexpression suppresses phenotypes induced by increased cAMP content in multiple genetic backgrounds. However, MSI1 does not inhibit cAMP synthesis or total cellular cAMP-dependent protein kinase (PKA) activity, nor does MSI1 stimulate expression of several cAMP-repressible genes critical for the acquisition of thermotolerance in the stationary phase. Our analysis indicates that yCAF-1 is dispensable for inhibition of hyperactive RAS by MSI1. We demonstrate that in the presence of the PKA regulatory subunit, BCY1, MSI1 inhibits phenotypes of a mutationally activated PKA catalytic subunit. These observations indicate that MSI1 affects PKA function in a BCY1-dependent manner via mechanisms other than direct overall inhibition of PKA catalytic activity. MSI1 appears to provide two distinct roles in chromatin modeling as a component of yCAF-1, and in the inhibition of RAS signaling by modulating PKA.
Zhu
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X
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Démolis
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N
Jacquet
M
M
Michaeli
T
T
D056504:Chromatin Assembly Factor-1; D002868:Chromosomal Proteins, Non-Histone; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013489:Suppression, Genetic; D018631:ras Proteins / Q000378:metabolism*
D056504:Chromatin Assembly Factor-1; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C061736:MSI1 protein, S cerevisiae; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins