Nucleic Acids Research, Vol 26, Issue 12 2865-2872, Copyright © 1998 by Oxford University Press
SJ Cok, CG Martin and JI Gordon
Inositol regulates transcription of Saccharomyces cerevisiae genes required
for de novo synthesis of acylCoAs and phospholipids. Removal of inositol
results in transcriptional activation by heterodimeric complexes of two
bHLH proteins, Ino2p and Ino4p. In the presence of inositol, transcription
is repressed by Opi1p. MyristoylCoA:protein N- myristoyltransferase (Nmt1p)
is an essential enzyme whose activity is influenced by cellular
myristoylCoA pool size and availability. nmt451Dp contains a
Gly451-->Asp substitution that produces temperature- dependent
reductions in affinity for myristoylCoA and associated reductions in
acylation of cellular N-myristoylproteins. The conditional lethality
produced by nmt1-451D is rescued at temperatures up to 33 degreesC by
withdrawal of inositol. We tested the hypothesis that N-myristoylproteins
function to regulate INO2, INO4 and/or OPI1 transcription, thereby
affecting the expression of inositol-sensitive genes that influence
myristoylCoA metabolism. The effect of nmt1-451D on INO2 , INO4 and OPI1
promoter activities was examined by introducing episomes, containing their
5' non-transcribed domains linked to reporters, into isogenic NMT1 and
nmt1-451D cells. The activity of INO2 is significantly higher, INO4
significantly lower and OPI1 unaffected in nmt1-451D cells, both in the
presence and absence of inositol. These changes are associated with a net
increase in expression of some inositol target genes, including FAS1 . FAS1
encodes one of the subunits of the fatty acid synthase complex that
catalyzes de novo acylCoA (including myristoylCoA) biosynthesis. Augmented
expression of FAS1 overcomes the kinetic defects in nmt451Dp. FAS1
expression is Ino2p-dependent in NMT1 cells at 24-33 degreesC. In contrast,
FAS1 expression becomes Ino2p-independent in nmt1-451D cells at
temperatures where efficient acylation of cellular N-myristoylproteins is
jeopardized. The ability to maintain expression of FAS1 in nmt1- 451Dino2
Delta cells suggests the existence of another transcription factor, or
factors, whose expression/activity is inversely related to overall levels
of cellular protein N-myristoy-lation. This factor is not functionally
identical to Ino2p since other inositol-responsive genes (e.g. CHO1 )
maintain INO2 -dependent expression in nmt1-451D cells.
ARTICLES
Transcription of INO2 and INO4 is regulated by the state of protein N- myristoylation in Saccharomyces cerevisiae
Department of Molecular Biology and Pharmacology, Box 8103, Washington University School of Medicine,660 South Euclid Avenue, St Louis, MO 63110, USA.
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