Existence of Mg2+-Dependent, Neutral Sphingomyelinase in Nuclei of Rat Ascites Hepatoma Cells1

Tamiya‐Koizumi, Keiko; Umekawa, Hayato; Yoshida, Shonen; Kojima, Kiyohide

doi:10.1093/oxfordjournals.jbchem.a122901

Cited by 50 publications

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“…Nuclear sphingosine kinase 2 (SPHK2), which converts SPH into sphingosine-1-phosphate, has recently been shown to modulate gene expression by regulating histone acetylation (20). In addition to SPHK2, other sphingolipid-metabolizing enzymes, such as sphingomyelinases and sphingomyelin synthases, have also been detected in nuclear extracts from different cell lines (1,2,46,72). Due to the hydrophobic nature of most sphingolipids, the nuclear expression of sphingolipid enzymes suggests that there is dynamic, localized production of bioactive lipids, which may have unique roles in nuclear processes independently from their cytoplasmic functions.…”

Section: Discussionmentioning

confidence: 99%

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Lucki

Bandyopadhyay

et al. 2012

Molecular and Cellular Biology

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Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is essential for steroidogenic gene transcription. Sphingosine (SPH) is a ligand for SF-1. Moreover, suppression of expression of acid ceramidase (ASAH1), an enzyme that produces SPH, increases the transcription of multiple steroidogenic genes. Given that SF-1 is a nuclear protein, we sought to define the molecular mechanisms by which ASAH1 regulates SF-1 function. We show that ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic AMP (cAMP) signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner. ASAH1 suppresses SF-1 activity by directly interacting with the receptor. Chromatin immunoprecipitation (ChIP) assays revealed that ASAH1 is recruited to the promoter of various SF-1 target genes and that ASAH1 and SF-1 colocalize on the same promoter region of the CYP17A1 and steroidogenic acute regulatory protein (StAR) genes. Taken together, these results demonstrate that ASAH1 is a novel coregulatory protein that represses SF-1 function by directly binding to the receptor on SF-1 target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription.

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Section: Discussionmentioning

confidence: 99%

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Lucki

Bandyopadhyay

et al. 2012

Molecular and Cellular Biology

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“…SM is metabolized to ceramide (CER) by sphingomyelinase (SMase), an enzyme first detected in the nuclear matrix of rat ascites hepatoma AH 7974 cells (33), and subsequently in the NE (34), chromatin (35), and nuclear matrix (29,35) of rat liver nuclei. Intact nuclei were proposed to express this enzyme in the NE, with translocation to the nuclear matrix in regenerating/proliferating rat liver (34).…”

Section: Nuclear Domains and Related Structuresmentioning

confidence: 99%

Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling

Ledeen

2008

Journal of Lipid Research

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Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes. Ceramide is further hydrolyzed to free fatty acid and sphingosine, the latter undergoing conversion to sphingosine phosphate by action of a specific nuclear kinase. Gangliosides are another type of sphingolipid found in the nucleus, members of the a-series of gangliotetraose gangliosides (GM1, GD1a) occurring in the NE and endonuclear compartments. GM1 in the inner membrane of the NE is tightly associated with a Na 1 / Ca 21 exchanger whose activity it potentiates, thereby contributing to regulation of Ca 21 homeostasis in the nucleus. This was shown to exert a cytoprotective role as absence or inactivation of this nuclear complex rendered cells vulnerable to apoptosis. This was demonstrated in the greatly enhanced kainite-induced seizure activity in knockout mice lacking gangliotetraose gangliosides. The pathology included apoptotic destruction of neurons in the CA3 region of the hippocampus. Ca 21 homeostasis was restored in these animals with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na 1 /Ca 21 exchanger. Some evidence suggests the presence of uncharged glycosphingolipids in the nucleus.-Ledeen, R. W. and G. Wu. Nuclear sphingolipids: metabolism and signaling.

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“…It has been known that cell nuclei contain a variety of enzymes generating lipid second messengers, such as sphingomyelinase (1), phospholipase A2 (2), PI 1 -specific phospholipase C (3-6) and lipid kinases (7). Growth factors seem to be able to affect the phosphoinositide metabolism in nuclei, suggesting a subtle regulation during cell activation (8,9).…”

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confidence: 99%

“…Partial hepatectomy was performed under light ether narcosis, and two-thirds of the liver was surgically removed according to the method of Higgins and Anderson (28). Livers were obtained as follows: control livers from nontreated and shamoperated rats and regenerating livers from partially hepatectomized rats (1,2,5,8,12,18,20,22,24,26,28,30, and 32 h post-hepatectomy).…”

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Nuclear ADP-ribosylation Factor (ARF)- and Oleate-dependent Phospholipase D (PLD) in Rat Liver Cells

Banno

Tamiya‐Koizumi

Oshima

et al. 1997

Journal of Biological Chemistry

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Two forms of phospholipase D (PLD) have been found to be present in nuclei isolated from rat hepatocytes by measuring phosphatidylbutanol produced from exogenous radiolabeled phosphatidylcholine in the presence of butanol. In nuclear lysates from either rat liver or ascites hepatoma AH 7974 cells, the PLD activity was markedly stimulated by a recombinant ADP-ribosylation factor (rARF) in the presence of the guanosine 5-O-(3-thiotriphosphate) (GTP␥S) and phosphatidylinositol 4,5-bisphosphate. ATP and phorbol-12-myristate 13-acetate had no synergistic effect on this PLD activity. On the other hand, the nuclear PLD was stimulated by unsaturated fatty acids, especially by oleic acid. The ARF-dependent nuclear PLD activity was increased in the S-phase of the regenerating rat liver after partial hepatectomy and also was much higher in AH 7974 cells than in the resting rat liver. In contrast, the levels of the oleate-dependent PLD activity remained constant throughout the cell cycle in liver regeneration. The intranuclear levels of the stimulating proteins of the nuclear PLD activity, e.g. ARF, RhoA, and protein kinase C␦ increased in the S-phase of the regenerating liver. These results suggested that the nuclear ARFdependent PLD activity may be associated with cell proliferation.It has been known that cell nuclei contain a variety of enzymes generating lipid second messengers, such as sphingomyelinase (1), phospholipase A2 (2), PI 1 -specific phospholipase C (3-6) and lipid kinases (7). Growth factors seem to be able to affect the phosphoinositide metabolism in nuclei, suggesting a subtle regulation during cell activation (8, 9). In addition, accumulation of diacylglycerol (DG) in nuclei and translocation of protein kinase C to them have been demonstrated in a variety of cell types (10, 11). A large rise in mass of DG, with only small changes in mass of phosphoinositides, suggested a source of DG other than polyphosphoinositides, for example, phosphatidylcholine (PC), in nuclei (12). A recent study (13) has demonstrated that phosphatidylethanol formation from phosphatidylcholine, which was specifically catalyzed by phospholipase D (PLD) in the presence of ethanol, was induced by PMA in nuclei isolated from kidney cells and that nuclei possess the ability to generate DG and phosphatidic acid through the PLD:phosphatidic acid phosphohydrolase pathway. Thus, upon cell stimulation with agonists, the enzymes involving PC metabolism are considered to be activated in the nucleus as well as in the plasma membrane.It was demonstrated that PLD activity can be regulated by several factors (14, 15); oleate, small G proteins (ARF and Rho family), phosphatidylinositol 4,5-bisphosphate (PIP 2 ), phosphatidylethanolamine (PE), Ca 2ϩ , protein kinase C, protein tyrosine kinase. Recently, two different types of PLD, oleatedependent and ARF-dependent, were isolated from rat brain membranes (16). The oleate-dependent PLD was purified from pig lung microsomes (17), and ARF-dependent PLD activity was found to be abundant in Golgi-enriched ...

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Existence of Mg2+-Dependent, Neutral Sphingomyelinase in Nuclei of Rat Ascites Hepatoma Cells1

Cited by 50 publications

References 0 publications

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling

Nuclear ADP-ribosylation Factor (ARF)- and Oleate-dependent Phospholipase D (PLD) in Rat Liver Cells

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