We showed previously that the abundance of serum albumin mRNA is decre
ased in H4-II-E rat hepatoma cells limited for a single essential amin
o acid (phenylalanine, methionine, leucine, or tryptophan). To define
the specificity of this phenomenon, we examined the effect of amino ac
id limitation on the abundance of mRNAs for 19 genes in the H4-II-E ce
lls. These genes included six genes whose expression is either complet
ely liver-specific or highly enriched in the liver compared with other
tissues [albumin, transthyretin (TTR), transferrin, carbamyl phosphat
e synthetase-I, urate oxidase, class I alcohol dehydrogenase], as well
as a number of ubiquitously expressed ''housekeeping'' genes. The res
ults indicated that the 19 genes could be divided into three classes b
ased on their response to amino acid limitation. Class I genes (the si
x liver-specific genes and alpha-tubulin) exhibit decreased expression
in response to amino acid limitation. The expression of class II gene
s [beta(2)- microglobulin, hypoxanthine-guanine phosphoribosyl transfe
rase (HPRT), H-ferritin, ubiquitin (UbB), insulin-like growth factor b
inding protein-4, HNF-1 alpha] is not significantly affected by amino
acid limitation. Class III genes [gadd153, beta-actin, ubiquitin (UbC)
, phosphoglycerate kinase-1, C/EBP alpha, C/EBP beta] exhibit increase
d expression in response to amino acid limitation. Thus, specific indu
ctive as well as repressive effects on gene expression are quite commo
n in amino acid-limited cells. The observation that all six genes whos
e expression is liver-specific exhibited decreased expression in amino
acid-limited cells suggests a common mode of regulation of these gene
s by amino acid availability. The strong induction by amino acid limit
ation of the C/EBP inhibitor gadd153 is of interest in this regard, as
increased levels of gadd153 could interfere with C/EBP, which is requ
ired for high expression of most liver-specific genes. To investigate
further the molecular mechanism for the decrease in albumin mRNA abund
ance, albumin nuclear transcript levels were quantified in control and
tryptophan-limited cells. Tryptophan limitation caused a decrease in
albumin nuclear transcript abundance, and this decrease preceded the d
ecrease in albumin mRNA, suggesting that the decrease in albumin mRNA
was caused at least partly by a decrease in albumin gene transcription
. Additional experiments with actinomycin D indicated that albumin mRN
A was also destabilized in the tryptophan-limited cells. Thus, the ove
rall results indicate that the decrease in albumin mRNA in the tryptop
han-limited cells is caused by a specific decrease in albumin nuclear
transcript abundance and destabilization of albumin mRNA.