Transcriptional regulation by lovastatin and 25-hydroxycholesterol in HepG2 cells and molecular cloning and expression of the cDNA for the human hepatic squalene synthase

Jiang, Guojian; McKenzie, Timothy; Conrad, D. G.; Shechter, Ishaiahu

doi:10.1016/s0021-9258(18)31461-3

Cited by 49 publications

(3 citation statements)

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“…There is also a coordinate increase in the mRNA levels of key enzymes of the isoprenoid/mevalonate pathway, such as HMG-CoA synthase, farnesyl diphosphate synthase, and squalene synthase (Harris et al, 1997). The transcription of these enzymes has been demonstrated to be regulated by sterol levels, via the sterol regulatory element binding proteins (SREBP) (Smith et al, 1988;Jiang et al, 1993;Ericsson et al, 1996;Vallet et al, 1996). SREBP are basic±helix± loop±helix leucine zipper transcription factors that are located in a hairpin loop conformation in the membranes of the endoplasmic reticulum and nucleus with the N-and C-termini in the cytosol (Yokoyama et al, 1993;Hua et al, 1993;Wang et al, 1994).…”

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confidence: 99%

Regulation of HMG-CoA Synthase and HMG-CoA Reductase by Insulin and Epidermal Growth Factor in HaCaT Keratinocytes

Harris

Höppner

Siefken

et al. 2000

Journal of Investigative Dermatology

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Synthesis of cholesterol, via the isoprenoid/mevalonate pathway, is required for keratinocyte growth and differentiation, and maintenance of the stratum corneum lipid lamellae. 3-hydroxy-3-methylglutaryl coenzyme A synthase catalyzes the first step in isoprenoid/mevalonate synthesis and under some conditions controls the flux into the pathway. We have investigated whether selected growth factors and hormones could increase 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA in keratinocytes. Northern blotting was used to demonstrate that 10 microg per ml insulin and 0.1 microg per ml epidermal growth factor both increased steady-state levels of 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA by 2.5 and 6-fold, respectively. Epidermal growth factor and insulin also increased 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme activity. 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter activity in a luciferase reporter construct was increased 2-fold by insulin and 2.9-fold by epidermal growth factor. When a mutation in the sterol regulatory element was introduced into the 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter, activity was not increased by insulin, but was increased by epidermal growth factor. Mutation of an AP-1 site in the 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter did not affect the increase in activity following treatment with insulin or epidermal growth factor. Therefore, 3-hydroxy-3-methylglutaryl coenzyme A synthase expression in keratinocytes is regulated by insulin and epidermal growth factor by different mechanisms. These results suggest a role for hormones and growth factors in the control of epidermal cholesterol synthesis.

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confidence: 99%

Regulation of HMG-CoA Synthase and HMG-CoA Reductase by Insulin and Epidermal Growth Factor in HaCaT Keratinocytes

Harris

Höppner

Siefken

et al. 2000

Journal of Investigative Dermatology

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“…However, it was not until 1988 that Sasiak and Rilling realized that two reactions in the pathway were catalyzed by a single enzyme, SQS, while purifying SQS to homogeneity from Saccharomyces cerevisiae [13]. Later on, in 1992 and 1993, rat SQS and human SQS were both cloned through cDNA using the same group of primers for both [14,15]. Lastly, in 2000, the crystal structure of human SQS was determined for the first time by Pandit et al [8].…”

Section: The Origins Of Sqsmentioning

confidence: 99%

Unveiling the Therapeutic Potential of Squalene Synthase: Deciphering Its Biochemical Mechanism, Disease Implications, and Intriguing Ties to Ferroptosis

Picón,

Skouta

2023

Cancers

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Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl pyrophosphate molecules, leading to the formation of squalene, which has been depicted as a highly effective oxygen-scavenging agent in in vitro studies. Recent studies have depicted this isoprenoid as a protective layer against ferroptosis due to its potential regulation of lipid peroxidation, as well as its protection against oxidative damage. Therefore, beyond its fundamental function, recent investigations have unveiled additional roles for SQS as a regulator of lipid peroxidation and programmed cell death pathways, such as ferroptosis—a type of cell death characterized by elevated levels of lipid peroxide, one of the forms of reactive oxygen species (ROS), and intracellular iron concentration. Notably, thorough explorations have shed light on the distinctive features that set SQS apart from other members within the isoprenoid synthase superfamily. Its unique biochemical structure, intricately intertwined with its reaction mechanism, has garnered significant attention. Moreover, considerable evidence substantiates the significance of SQS in various disease contexts, and its intriguing association with ferroptosis and lipid peroxidation. The objective of this report is to analyze the existing literature comprehensively, corroborating these findings, and provide an up-to-date perspective on the current understanding of SQS as a prospective therapeutic target, as well as its intricate relationship with ferroptosis. This review aims to consolidate the knowledge surrounding SQS, thereby contributing to the broader comprehension of its potential implications in disease management and therapeutic interventions.

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“…Thus, FPP is involved in both cellular growth and signaling (12,13). The regulation of FPP formation and its further conversion to sterols has been extensively investigated (14)(15)(16)(17)(18)(19)(20)(21). The significance of the subcellular localization of the enzymes involved in the biosynthesis and utilization of FPP is not well understood.…”

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confidence: 99%

Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism

Gupta

Mehan

Tansey

et al. 1999

Journal of Lipid Research

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Transcriptional regulation by lovastatin and 25-hydroxycholesterol in HepG2 cells and molecular cloning and expression of the cDNA for the human hepatic squalene synthase

Cited by 49 publications

References 0 publications

Regulation of HMG-CoA Synthase and HMG-CoA Reductase by Insulin and Epidermal Growth Factor in HaCaT Keratinocytes

Regulation of HMG-CoA Synthase and HMG-CoA Reductase by Insulin and Epidermal Growth Factor in HaCaT Keratinocytes

Unveiling the Therapeutic Potential of Squalene Synthase: Deciphering Its Biochemical Mechanism, Disease Implications, and Intriguing Ties to Ferroptosis

Differential binding of proteins to peroxisomes in rat hepatoma cells: unique association of enzymes involved in isoprenoid metabolism

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