High impact information on UPC2

• The C-terminal regions of Upc2p and Ecm22p, which contained activation domains, also conferred regulation in response to sterol levels [1].
• We identified 9 genes as responsive to UPC2 that were also induced under anaerobiosis, when sterol uptake is essential [2].
• Concomitant with the increase in secretion following cholesterol uptake by upc2 strains, approximately 5% of secreted apoE was associated with lipid; polar and non-polar lipids were detected in this lipoprotein fraction [3].
• Secretion of apoE was achieved only by the use of a mutant (upc2) strain of yeast with the phenotype of enhanced uptake and intracellular esterification of exogenous cholesterol [3].
• Indeed, upon sterol depletion, Upc2p no longer required Hap1p to activate ERG genes [4].

Biological context of UPC2

• A search of the C. albicans genome identified a single homolog of the S. cerevisiae transcription factor genes UPC2 (ScUPC2) and ECM22 (ScECM22) that have been associated with regulation of ergosterol biosynthesis [5].
• Importantly, the purified DNA binding domain of Upc2p bound in vitro to putative sterol response elements in the ERG2 promoter, suggesting that Upc2p increases the expression of the ERG genes by directly binding to their promoters [6].
• Since these proteins are very similar, the effect of mutations in the YLR228c open reading frame (ORF) was compared with like alterations in UPC2 [7].
• We have identified the transcriptional activation domains of Upc2p and Ecm22p and found that UPC2-1, a mutation that allows cells to take up sterols aerobically, increased the potency of the activation domain [1].
• Upc2p and Ecm22p may thereby coordinately regulate genes involved in sterol homeostasis in yeast [8].

Associations of UPC2 with chemical compounds

• UPC2 itself was up-regulated under these conditions and was required for aerobic sterol influx [2].
• Conversely, overexpression of Upc2p increased resistance to ketoconazole, fluconazole, and fluphenazine [6].

Other interactions of UPC2

• UPC2 and ECM22 belong to a Zn(2)-Cys(6) family of fungal transcription factors and have been implicated in the regulation of sterol synthesis in Saccharomyces cerevisiae and Candida albicans [9].
• Indeed, ectopic expression of MOX4 in aerobic cells resulted in partially constitutive expression of DAN1 [10].
• Additional promoter searches revealed that nearly one-third of the anaerobically induced genes contain an AR1 site(s) for the Upc2 transcription factor, suggesting that Upc2 and Rox1 regulate the majority of anaerobically induced genes in S. cerevisiae [11].
• As reported elsewhere, Mox4 is a heme-inhibited activator, and Mot3 is a heme-induced repressor of the DAN/TIR genes (but not of TIP1) [12].

Analytical, diagnostic and therapeutic context of UPC2

• Upon inducing conditions, Upc2p levels increased, and chromatin immunoprecipitation experiments revealed more Upc2p at promoters even when the activation/regulatory domains were tethered to a different DNA-binding domain [1].

References