Disease relevance of HMG1

• A C-terminal-truncated fragment of the U. maydis HMG-CoA reductase gene was shown to be expressed in Escherichia coli in a catalytically active form [1].
• HMG-CoA reductase inhibitors are very efficient in long-term control of atherogenesis acting by different mechanisms not fully established [2].

High impact information on HMG1

• When HMG-domain proteins such as HMG1, IXR (intrastrand-crosslink recognition) protein from yeast, or human upstream-binding factor (hUBF) bind cisplatin intrastrand crosslinks, they can be diverted from their natural binding sites on the genome and shield the adducts from excision repair [3].
• The identification of Cod1p is especially intriguing in light of the role Ca(2+) plays in the regulated degradation of mammalian HMGR [4].
• The integral ER membrane protein HMG-CoA reductase (HMGR) is a key enzyme of the mevalonate pathway from which sterols and other essential molecules are produced [4].
• The yeast HMG-CoA reductase isozyme Hmg2p undergoes stringently regulated degradation by machinery that is also required for ER quality control [5].
• Elevated levels of certain membrane proteins, including the sterol biosynthetic enzyme HMG-CoA reductase, induce proliferation of the endoplasmic reticulum [6].

Biological context of HMG1

• The previously uncharacterized Pob3 sequence has significant amino acid sequence similarity with an HMG1-like protein from vertebrates [7].
• Assays of HMG-CoA reductase activity indicated that the point mutations destroy most if not all of the activity encoded by HMG1 [8].
• We also revealed that the HMG1 promoter region between -500 and -376 was important in the transcriptional activation by Hap1 [9].
• Involvement of the mutated Hap1 in the differential gene expression between strain K7 and strain X2180 was further confirmed by a lacZ reporter assay of HMG1, one of the Hap1-regulated genes [9].
• The protein has sequence similarity to HMG1, specifically binds crossing DNA structures, and serves as a negative transcriptional regulator of a small family of genes that are activated by the SWI/SNF chromatin-remodeling complex [10].

Anatomical context of HMG1

• These nuclear-associated, paired membranes have been named "karmellae." In strains that overproduced the HMG1 isozyme, HMG-CoA reductase was present in the karmellar layers [11].
• Yeast express two HMG-CoA reductase isozymes, and each isozyme induces a morphologically distinct proliferation of the endoplasmic reticulum [12].
• In all eukaryotic cells that have been examined, specific membrane arrays are induced in response to increased levels of the ER membrane protein, HMG-CoA reductase [12].
• Importantly, the amino-terminal sequence of one of the proteins, NHP6, has significant (60%) identity with a stretch of amino acids in calf thymus HMG1 [13].
• HMG1 transfection complexes were not toxic to cultured cells, even at high concentrations [14].

Associations of HMG1 with chemical compounds

• However, cells containing a mutant allele of either HMG1 or HMG2 are viable but are more sensitive to compactin, a competitive inhibitor of HMG-CoA reductase, than are wild-type cells [15].
• The two yeast genes for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, HMG1 and HMG2, each encode a functional isozyme [8].
• Our results demonstrate that palmitoleic acid (16:1) acts as a rate-limiting positive regulator and that ergosterol acts as a potent inhibitor of sterol production in strains which possess only the HMGR1 isozyme (HMG1 hmg2) [16].
• In strains which contain only the HMGR2 isozyme (hmg1 HMG2), sterol production was inhibited by oleic acid (18:1) and to a lesser degree by ergosterol [16].
• Two recessive alleles of ERG10 and three temperature-sensitive recessive alleles of HMG1 (3-hydroxy-3-methyl-glutaryl-CoA reductase isoenzyme 1) were isolated in a screen for mevalonate auxotrophs in Saccharomyces cerevisiae [17].

Other interactions of HMG1

• Cells containing mutant alleles of both HMG1 and HMG2 are unable to undergo spore germination and vegetative growth [15].
• The predicted SIN1/SPT2 protein has a distinctive amino acid composition (45% charged residues, 25% basic and 20% acidic) and has similarity to the mammalian HMG1 protein, a nonhistone component of chromatin [18].
• Taken together, the data indicate that HMO1 is likely to be the homolog of HMG1/2 in higher cells and that it plays an important role in genome maintenance [19].
• The Saccharomyces cerevisiae ACP2 gene encodes an essential HMG1-like protein [20].
• SHM1: a multicopy suppressor of a temperature-sensitive null mutation in the HMG1-like abf2 gene [21].

Analytical, diagnostic and therapeutic context of HMG1

• Immunoblotting experiments ruled out the simple possibility that differences in the amounts of the various chimeric HMG-CoA reductase proteins was responsible for the altered cellular responses [12].
• Transmission electron microscopy and immunocytochemical studies of yeast: analysis of HMG-CoA reductase overproduction by electron microscopy [22].
• Northern blot analysis reveals a single transcript of 2.4 kb in leaves and seedlings, which presumably corresponds to the expression of the HMG1 gene [23].
• A. thaliana contains two different HMG-CoA reductase genes (HMG1 and HMG2), as estimated by gene cloning and Southern blot analysis [23].
• Sequence analysis of this clone revealed a coding region that shares a high degree of homology with the carboxyl-terminal domain of hamster HMG-CoA reductase [24].

References