Xy. Zhu et al., MSI1 suppresses hyperactive RAS via the cAMP-dependent protein kinase and independently of chromatin assembly factor-1, CURR GENET, 38(2), 2000, pp. 60-70
RAS hyperactivation in the yeast Saccharomyces cerevisiae leads to multiple
nutritional growth defects associated with overstimulation of the cAMP sig
naling pathway. Hyperactive RAS can be suppressed by overexpression of MSI1
, a subunit of chromatin assembly factor-1 (yCAF-1). MSI1 overexpression su
ppresses phenotypes induced by increased cAMP content in multiple genetic b
ackgrounds. However, MSI1 does not inhibit cAMP synthesis or total cellular
cAMP-dependent protein kinase (PKA) activity, nor does MSI1 stimulate expr
ession of several cAMP-repressible genes critical for the acquisition of th
ermotolerance in the stationary phase. Our analysis indicates that yCAF-1 i
s dispensable for inhibition of hyperactive RAS by MSI1. We demonstrate tha
t in the presence of the PKA regulatory subunit, BCY1, MSI1 inhibits phenot
ypes of a mutationally activated PKA catalytic subunit. These observations
indicate that MSI1 affects PKA function in a BCY1-dependent manner via mech
anisms other than direct overall inhibition of PKA catalytic activity. MSI1
appears to provide two distinct roles - in chromatin modeling as a compone
nt of yCAF-1, and in the inhibition of RAS signaling by modulating PKA.