Regulation of phosphatidylcholine homeostasis by calcium-independent phospholipase A2

Barbour, Suzanne E.; Kapur, Anita; Deal, Clifford L

doi:10.1016/s1388-1981(99)00078-5

Cited by 83 publications

(93 citation statements)

References 42 publications

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“…Our results suggested that there may be excess capacity for PtdCho synthesis, represented by the copy number of the rate-controlling enzymes in brain (and other tissues), and the loss of about one-third of the CCT transcripts does not have a gross effect. We were somewhat surprised that disruption of CCT␤2 expression in mice did not have any overt effect brain development, content, or morphology in light of recent reports that CCT␤2 expression was selectively upregulated in the hippocampus by the neuropeptide arginine-vasopressin (4)(5)(6)(7)(8) (63) and during neurite outgrowth of NGF-treated PC12 cells (12). We addressed this inconsistency by using our real-time PCR tools to quantify the changes in the CCT transcript levels in PC12 cells stimulated with NGF to determine whether the information obtained by using an immortalized cell line was distinctly different from that obtained from the whole animal.…”

Section: Fig 3 Expression Of Cct␣ and Cct␤ Mrnas In Tissues Frommentioning

confidence: 99%

“…Acceleration of PtdCho synthesis by the overexpression of CCT is counteracted by the ability of cells to degrade PtdCho to glycerophosphocholine and to maintain a constant cellular phospholipid content (5,53). These studies reveal the existence of a homeostatic mechanism(s) for biochemical control over membrane phospholipid biosynthesis (5,7,14), but they shed no light on the role of the specific CCT isoforms or their regulatory domains in cell physiology.…”

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confidence: 99%

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Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Jackowski

Rehg

Zhang³

et al. 2004

Molecular and Cellular Biology

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There are two mammalian genes that encode isoforms of CTP:phosphocholine cytidylyltransferase (CCT), a key rate-controlling step in membrane phospholipid biogenesis. Quantitative determination of the CCT transcripts reveals that CCT␣ is ubiquitously expressed and is found at the highest levels in the testis and lung, with lower levels in the liver and ovary. CCT␤2 is a very minor isoform in most tissues but is significantly expressed in the brain, lung, and gonads. CCT␤3 is the third isoform recently discovered in mice and is expressed in the same tissues as CCT␤2, with its highest level in testes. We investigated the role(s) of CCT␤2 by generating knockout mice. The brains and lungs of mice lacking CCT␤2 expression did not exhibit any overt defects. On the other hand, a large percentage of the CCT␤2 ؊/؊ females were sterile and their ovaries exhibited defective ovarian follicle development. The proportion of female CCT␤2 ؊/؊ mice with defective ovaries increased as the animals aged. The rare litters born from CCT␤2 ؊/؊ ؋ CCT␤2 ؊/0 matings had the normal number of pups. The abnormal ovarian histopathology was characterized by disorganization of the tissue in young adult mice and absence of follicles and ova in older mice, along with interstitial stromal cell hyperplasia which culminated in the emergence of tubulostromal ovarian tumors by 16 months of age. Grossly defective CCT␤2 ؊/؊ ovaries were associated with high follicle-stimulating (FSH) and luteinizing (LH) hormone levels. Male CCT␤2 ؊/0 mice exhibited progressive multifocal testicular degeneration and reduced fertility but had normal FSH and LH levels. Thus, the most notable phenotype of CCT␤2 knockout mice was gonad degeneration and reproductive deficiency. The results indicate that although CCT␤2 is expressed at very low levels compared to the ␣-isoform, loss of CCT␤2 expression causes a breakdown in the gonadal response to hormonal stimulation.Phosphatidylcholine (PtdCho) is a major component of biological membranes in higher eukaryotes and is also secreted by specialized tissues for important extracellular tasks. CTP: phosphocholine cytidylyltransferase (CCT) is a key rate-controlling step in the major biosynthetic pathway leading to PtdCho in most tissues (for reviews, see references 15, 17, and 36). In mammals there are two genes, Pcyt1a (formerly Cptct), located on murine chromosome 16, and Pcyt1b, located on the X chromosome, that encode proteins termed CCT␣ and CCT␤, respectively (35, 38). The two genes exhibit tissuespecific expression, with CCT␣ predominating in most tissues and CCT␤ being most abundant in brain tissue (32). Two transcripts arise from the Pcyt1a gene that encode the identical CCT␣ protein. Alternate splicing of the X-linked Pcyt1b gene directs the synthesis of two mRNAs that encode the CCT␤2 and CCT␤3 isoforms in mice (32,35,38). CCT␤3 is 28 residues shorter at the amino terminus than CCT␤2 due to transcript initiation at an alternate first exon (32). In humans, intron retention gives rise to a CCT␤1 transcript found in the exp...

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Section: Fig 3 Expression Of Cct␣ and Cct␤ Mrnas In Tissues Frommentioning

confidence: 99%

mentioning

confidence: 99%

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Jackowski

Rehg

Zhang³

et al. 2004

Molecular and Cellular Biology

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“…Phospholipase A 2 Activity Assays-PLA 2 activity was assayed using well established methods (5,22). Briefly, cell homogenates were prepared in 10 mM HEPES, pH 7.4, 0.34 M sucrose, 10 g/ml leupeptin, 10 g/ml aprotinin, 1 mM phenylmethylsulfonyl fluoride (assay homogenization buffer), and were lysed by sonication.…”

Section: Materials-cho-k1mentioning

confidence: 99%

“…Overexpression of CT␣ in COS, CHO-K1, and HeLa cells increased PC synthesis, yet PC mass remained relatively constant because of increased catabolism (5-7). We showed that iPLA 2 activity and protein were up-regulated in CHO cells that overexpressed CT␣ (5), suggesting that this enzyme was responsible for maintaining membrane phospholipid mass by modulating the rate of PC catabolism. In addition to its role in maintaining glycerophospholipid homeostasis, iPLA 2 is also involved in other cellular processes, including acyl chain remodeling, apoptosis, and eicosanoid production (8 -10).…”

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confidence: 93%

Cell Cycle Dependence of Group VIA Calcium-independent Phospholipase A2 Activity

Manguikian

Barbour

2004

Journal of Biological Chemistry

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2 activity, suggesting that regulation of this enzyme contributes to phospholipid accumulation. The levels of 80 kDa iPLA 2 protein do not change and thus cannot account for changes in enzyme activity. Reverse transcriptase and real-time PCR experiments show that splice variant iPLA 2 mRNAs are preferentially expressed during G 2 /M. Immunoblot analyses with an antibody directed against the N terminus of iPLA 2 revealed a ϳ50 kDa protein that is of appropriate size to be the truncated protein encoded by the ankyrin-iPLA 2 -1 splice variant mRNA. The levels of truncated iPLA 2 protein were high in cells in late G 1 and S phase cells that had low iPLA 2 activity and low in G 2 /M cells that had high iPLA 2 activity. The truncated protein co-immunoprecipitated with full-length iPLA 2 , indicating a physical interaction between the two proteins. Together, these data suggest that truncated iPLA 2 proteins associate with active iPLA 2 and down-regulate its activity during G 1 . This down-regulation may contribute to phospholipid accumulation during the cell cycle.

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“…sPLA 2 has no apparent selectivity requirement in vitro [75,[78][79]. Furthermore, iPLA 2 appears to be involved in membrane phospholipid homeostasis and is up-regulated in response to increased phosphatidylcholine synthesis [80][81].…”

Section: Fabp7/fatty Acid Mechanisms Controlling Malignant Glioma Migmentioning

confidence: 99%

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Elsherbiny

Emara

Godbout

2013

Progress in Lipid Research

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Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma.

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Regulation of phosphatidylcholine homeostasis by calcium-independent phospholipase A2

Cited by 83 publications

References 42 publications

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Disruption of CCTβ2 Expression Leads to Gonadal Dysfunction

Cell Cycle Dependence of Group VIA Calcium-independent Phospholipase A2 Activity

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

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