Disease relevance of HMGCS2

• HMGCS2 protein expression is down-regulated preferentially in moderately and poorly differentiated carcinomas [1].
• Ketogenic HMGCS2 Is a c-Myc Target Gene Expressed in Differentiated Cells of Human Colonic Epithelium and Down-Regulated in Colon Cancer [1].
• A double mutant was constructed in Myxococcus xanthus by deletion of genes involved in leucine degradation and disruption of mvaS encoding the 3-hydroxy-3-methylglutaryl-coenzyme A synthase [2].

High impact information on HMGCS2

• Up-regulation of genes (Hmgcs2, Ech1, Acox1, Pcca, Lpl and Acaa2) was verified and confirmed by quantitative real time PCR [3].
• These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin [4].
• This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis [4].
• Sequencing of the entire coding region of the HMGCS2 gene revealed two missense mutations, G212R and R500H [5].
• Whereas wild-type cDNA of the HMGCS2 gene reverted the auxotrophy for mevalonate, the cDNAs of the mutants did not [5].

Biological context of HMGCS2

• The human mHS locus (HMGCS2) on chromosome 1p12-13 spans 25 kb and contains 10 exons [6].
• An FKHRL1-responsive sequence AAAAATA, located 211 bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis [4].

Anatomical context of HMGCS2

• Accordingly, immunohistochemistry with specific antibodies shows that HMGCS2 is expressed mainly in differentiated cells of human colonic epithelium [1].

Associations of HMGCS2 with chemical compounds

• In contrast, HepG2 cells seemed to be resistant to PPARalpha activation by 13-HPODE because no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed [7].
• HMGCS2, the gene that regulates ketone body production, is expressed in liver and several extrahepatic tissues, such as the colon [1].
• A previously undescribed 'feed-forward' regulation was observed in which elevated levels of HMG-CoA synthase, the enzyme catalysing the synthesis of the HMG-CoA reductase substrate, induced elevated levels of hmgl+ protein in the cell and conferred partial resistance to lovastatin [8].

Other interactions of HMGCS2

• Based on these findings, we propose that ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2 [1].

References