Involvement of specific proteins (Sp1/Sp3) and nuclear factor Y in basal transcription of the distal promoter of the rat pyruvate carboxylase gene in β-cells

Sunyakumthorn, Piyanate; Boonsaen, Thirajit; Boonsaeng, Vichai; Wallace, John C.; Jitrapakdee, Sarawut

doi:10.1016/j.bbrc.2005.01.108

Cited by 17 publications

(22 citation statements)

References 28 publications

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“…Unfortunately, there was no data for PC mRNA in adipose tissues of these transgenic mice [12]. For the distal promoter, specific proteins (Sp1and Sp3) and the nuclear factor Y (NF-Y) are the major transcription factors that positively and negatively regulate PC transcription under basal conditions, respectively [38].…”

Section: Tissue-specific Control Of Pcmentioning

confidence: 99%

“…In rats, the PC gene possesses two tissue-specific promoters, the proximal and distal promoters [13], and it is the distal promoter which is active and inducible by glucose in b-cells [37]. Recent characterization of the distal promoter of the rat PC gene has shown that the Sp1/Sp3 transcription factor may be important in regulating transcriptional activity of the PC gene during induction by glucose [38]. Pyruvate could enter mitochondria either to undergo decarboxylation by PDH or carboxylation by PC.…”

Section: The Role Of Pc In Pancreatic B-cellsmentioning

confidence: 99%

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Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Jitrapakdee

Vidal-Puig

Wallace

2006

Cell. Mol. Life Sci.

141

120

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Pyruvate carboxylase (PC) catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate. PC serves an anaplerotic role for the tricarboxylic acid cycle, when intermediates are removed for different biosynthetic purposes. In liver and kidney, PC provides oxaloacetate for gluconeogenesis. In adipocytes PC is involved in de novo fatty acid synthesis and glyceroneogenesis, and is regulated by the peroxisome proliferator-activated receptor-gamma, suggesting that PC is involved in the metabolic switch controlling fuel partitioning toward lipogenesis. In islets, PC is necessary for glucose-induced insulin secretion by providing oxaloacetate to form malate that participates in the 'pyruvate/malate cycle' to shuttle 3C or 4C between mitochondria and cytoplasm. Hyperglycemia and hyperlipidemia impair this cycle and affect glucose-stimulated insulin release. In astrocytes, PC is important for de novo synthesis of glutamate, an important excitatory neurotransmitter supplied to neurons. Transcriptional studies of the PC gene pinpoint some transcription factors that determine tissue-specific expression.

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Section: Tissue-specific Control Of Pcmentioning

confidence: 99%

Section: The Role Of Pc In Pancreatic B-cellsmentioning

confidence: 99%

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Jitrapakdee

Vidal-Puig

Wallace

2006

Cell. Mol. Life Sci.

141

120

View full text Add to dashboard Cite

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“…It has also been demonstrated that Sp1 and Sp3, both of which are major members of Sp1 transcription factors, are ubiquitously expressed in most tissues [8], as shown by their equivalent binding to GC boxes [9]. However, in mammalian cells, Sp1 typically functions as a transcriptional activator, whereas Sp3 functions as either an activator or a repressor [10].…”

Section: Discussionmentioning

confidence: 99%

“…GC box is the specific binding site of Sp1 transcription factors, especially Sp1 and Sp3 [8][9][10]. It has also been demonstrated that Sp1 and Sp3, both of which are major members of Sp1 transcription factors, are ubiquitously expressed in most tissues [8], as shown by their equivalent binding to GC boxes [9].…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of the minimal promoter of <italic>Mipu1</italic>: the role of GC boxes in the regulation of basal transcription

Lv¹,

Tang²,

Li³

et al. 2009

ABBS

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Mipu1, a novel gene encoding a KRAB/C2H2 zincfinger protein, was first reported to be up-regulated in myocardial ischemia-reperfusion injury, functioning to protect cells against oxidative stress. To map the promoter region of the gene and to understand its regulation, we identified the transcription start site and revealed that the 1366-bp fragment upstream of the transcription start site possesses promoter activity. Deletion constructs of the 5 0 -flanking region of Mipu1 lead to the identification of a minimal promoter, in which neither a TATA box nor a CAAT box was detected. Two GC boxes were found; however, they are the specific binding sites for Sp1-family transcription factors. Mutations in these GC boxes resulted in the total loss of Mipu1 minimal promoter activity. Finally, WP631, an Sp1-family-specific inhibitor, was found to decrease the promoter activity in a dose-dependent manner, indicating that the GC boxes are essential for the activity of the Mipu1 minimal promoter activity.

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“…Its transcription is influenced by some of the same transcription factors that influence the transcription of PC (8,(55)(56)(57), and both PC and mGPD are down-regulated in human islets isolated from subjects with type 2 diabetes (25), similarly to islets isolated from rodent models of type 2 diabetes (43, 58 -60, 62). Because the level of mGPD is as high in normal human islets as in normal rat islets (Table 3), this is consistent with the idea that the low PC in human islets is specific for human islets.…”

Section: Human Islets Rat Isletsmentioning

confidence: 99%

Differences between Human and Rodent Pancreatic Islets

MacDonald

Longacre

Stoker

et al. 2011

Journal of Biological Chemistry

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Anaplerosis, the net synthesis in mitochondria of citric acid cycle intermediates, and cataplerosis, their export to the cytosol, have been shown to be important for insulin secretion in rodent beta cells. However, human islets may be different. We observed that the enzyme activity, protein level, and relative mRNA level of the key anaplerotic enzyme pyruvate carboxylase (PC) were 80 -90% lower in human pancreatic islets compared with islets of rats and mice and the rat insulinoma cell line INS-1 832/13. Activity and protein of ATP citrate lyase, which uses anaplerotic products in the cytosol, were 60 -75% lower in human islets than in rodent islets or the cell line. In line with the lower PC, the percentage of glucose-derived pyruvate that entered mitochondrial metabolism via carboxylation in human islets was only 20 -30% that in rat islets. This suggests human islets depend less on pyruvate carboxylation than rodent models that were used to establish the role of PC in insulin secretion. Human islets possessed high levels of succinyl-CoA:3-ketoacid-CoA transferase, an enzyme that forms acetoacetate in the mitochondria, and acetoacetyl-CoA synthetase, which uses acetoacetate to form acyl-CoAs in the cytosol. Glucose-stimulated human islets released insulin similarly to rat islets but formed much more acetoacetate. ␤-Hydroxybutyrate augmented insulin secretion in human islets. This information supports previous data that indicate beta cells can use a pathway involving succinyl-CoA:3-ketoacid-CoA transferase and acetoacetyl-CoA synthetase to synthesize and use acetoacetate and suggests human islets may use this pathway more than PC and citrate to form cytosolic acyl-CoAs.Understanding the enzymatic makeup of human pancreatic islets is fundamental to developing strategies for designing artificial beta cells and beta cells differentiated from stem cells as treatments for type 1 diabetes, as well as modulating beta cell metabolism for the treatment of type 2 diabetes. Until recently, most of the information about normal insulin secretion came from studies of rodent islets or clonal cell lines. Although a recent study showed human pancreatic islets respond to insulin secretagogues similarly to rodent islets (1), what is still unknown is whether the use of intracellular pathways of secretagogue metabolism is the same in human islets as in rodent islets and cell lines. During the last few years, human islet preparations from human donors have become more readily available to researchers. By studying the levels of enzymes, the functional units of metabolism, the recent abundant supply of human islets has enabled our laboratory to discover clues suggesting differences in metabolic pathways between pancreatic islets of humans and rodents that have implications for better understanding normal human beta cell physiology.Anaplerosis, the biosynthesis of citric acid cycle intermediates (2), is widely believed to be important for insulin secretion (3). Pyruvate carboxylase (PC) 2 is the key anaplerotic enzyme in this process ...

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Involvement of specific proteins (Sp1/Sp3) and nuclear factor Y in basal transcription of the distal promoter of the rat pyruvate carboxylase gene in β-cells

Cited by 17 publications

References 28 publications

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Identification and characterization of the minimal promoter of <italic>Mipu1</italic>: the role of GC boxes in the regulation of basal transcription

Differences between Human and Rodent Pancreatic Islets

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Involvement of specific proteins (Sp1/Sp3) and nuclear factor Y in basal transcription of the distal promoter of the rat pyruvate carboxylase gene in β-cells

Cited by 17 publications

References 28 publications

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Anaplerotic roles of pyruvate carboxylase in mammalian tissues

Identification and characterization of the minimal promoter of &lt;italic&gt;Mipu1&lt;/italic&gt;: the role of GC boxes in the regulation of basal transcription

Differences between Human and Rodent Pancreatic Islets

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Identification and characterization of the minimal promoter of <italic>Mipu1</italic>: the role of GC boxes in the regulation of basal transcription