Abstract
Eukaryotes utilize fatty acids by beta-oxidation, which occurs in the mitochondria and peroxisomes in higher organisms and in the peroxisomes in yeast. The AMP-activated protein kinase regulates this process in mammalian cells, and its homolog Snf1, together with the transcription factors Adr1, Oaf1, and Pip2, regulates peroxisome proliferation and beta-oxidation in yeast. A constitutive allele of Adr1 (Adr1(c)) lacking the glucose- and Snf1-regulated phosphorylation substrate Ser-230 was found to be Snf1-independent for regulation of peroxisomal genes. In addition, it could compensate for and even suppress the requirement for Oaf1 or Pip2 for gene induction. Peroxisomal genes were found to be regulated by oleate in the presence of glucose, as long as Adr1(c) was expressed, suggesting that the Oaf1/Pip2 heterodimer is Snf1-independent. Consistent with this observation, Oaf1 binding to promoters in the presence of oleate was not reduced in a snf1Delta strain. Exploring the mechanism by which Adr1(c) permits Snf1-independent peroxisomal gene induction, we found that strength of promoter binding did not correlate with transcription, suggesting that stable binding is not a prerequisite for enhanced transcription. Instead, enhanced transcriptional activation and suppression of Oaf1, Pip2, and Snf1 by Adr1(c) may be related to the ability of Adr1(c) to suppress the requirement for and enhance the recruitment of transcriptional coactivators in a promoter- and growth medium-dependent manner.
Highlights
In the presence of fatty acids, these genes are further induced leading to active metabolism of exogenous fatty acids and peroxisome biogenesis [3,4,5]
Adr1c and Adr1 Overexpression Overcome the Lack of OAF1 or PIP2 and SNF1 to Induce Gene Expression on Oleate—Adr1c and overexpression of WT Adr1 led to the expression of Adr1, Cat8-co-dependent genes on glucose, as well as increased induction upon derepression, compared with WT Adr1 [15, 21,22,23, 43]
We have shown that when Adr1 is constitutively active because of mutation of Ser-230 (Adr1c), Snf1 is not necessary for peroxisomal gene expression
Summary
In the presence of fatty acids, these genes are further induced leading to active metabolism of exogenous fatty acids and peroxisome biogenesis [3,4,5]. The mammalian AMP-activated protein kinase and its yeast homolog, Snf protein kinase, are important for both peroxisome proliferation in the presence of fatty acids, as well as -oxidation [6]. The pathway further requires the coordinate action of three transcription factors, Adr, Oaf, and Pip (6 – 8). A fourth transcription factor, Oaf, has been identified as a transcriptional repressor in the presence of oleate [13]. How these transcription factors interact with each other and with the upstream signaling pathways for peroxisome proliferation is unknown. Adr is phosphorylated at Ser-230 by an unknown protein kinase under repressing conditions, when it is inactive [23]. CKY19 EAY14 EAY12 EAY15 KKTY04 TYY540 TYY541 TYY542 TYY543 CKY13 CKY26 CKY7 SRY1 SRY3 SRY2 SRY5 SRY67 RBY34 RBY36 Z1603
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