Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

Alderson, Nathan L.; Hama, Hiroko

doi:10.1194/jlr.m800666-jlr200

Cited by 26 publications

(23 citation statements)

References 37 publications

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“…The fatty acid was catalyzed by fatty acid 2-hydroxylase and converted to 2-hydroxy fatty acid (hFA) and then incorporated into hFAceramide and complex hFA-sphingolipids [45]. A recent study showed that upregulation of fatty acid 2-hydroxylase could inhibit dibutyryl-cAMP-induced cell cycle exit in D6P2T Schwannoma cells [46]. The higher levels of hFA-sphingolipids indicate a higher expression level of fatty acid 2-hydroxylase, which may affect cancer cell growth in breast cancer patients.…”

Section: Resultsmentioning

confidence: 99%

Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients

Qiu

Zhou

et al. 2013

IJMS

101

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Breast cancer accounts for the largest number of newly diagnosed cases in female cancer patients. Although mammography is a powerful screening tool, about 20% of breast cancer cases cannot be detected by this method. New diagnostic biomarkers for breast cancer are necessary. Here, we used a mass spectrometry-based quantitative metabolomics method to analyze plasma samples from 55 breast cancer patients and 25 healthy controls. A number of 30 patients and 20 age-matched healthy controls were used as a training dataset to establish a diagnostic model and to identify potential biomarkers. The remaining samples were used as a validation dataset to evaluate the predictive accuracy for the established model. Distinct separation was obtained from an orthogonal partial least squares-discriminant analysis (OPLS-DA) model with good prediction accuracy. Based on this analysis, 39 differentiating metabolites were identified, including significantly lower levels of lysophosphatidylcholines and higher levels of sphingomyelins in the plasma samples obtained from breast cancer patients compared with healthy controls. Using logical regression, a diagnostic equation based on three metabolites (lysoPC a C16:0, PC ae C42:5 and PC aa C34:2) successfully differentiated breast cancer patients from healthy controls, with a sensitivity of 98.1% and a specificity of 96.0%.

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Section: Resultsmentioning

confidence: 99%

Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients

Qiu

Zhou

et al. 2013

IJMS

101

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“…It is of interest to note that cultured rat cortical neurons showed robust, but transient, upregulation of Fa2h expression during differentiation (our unpublished data). We previously showed that FA2H modulates the cAMP signaling pathway in Schwannoma cells (Alderson and Hama 2009). It is conceivable that an FA2H-dependent regulatory mechanism for cAMP signaling exists in differentiating neurons.…”

Section: Discussionmentioning

confidence: 99%

Central nervous system dysfunction in a mouse model of Fa2h deficiency

Potter

Kern

Fullbright

et al. 2011

Glia

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122

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Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N-acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants, Fa2h−/− mice (Fa2h deleted in all cells by germline deletion) and Fa2hflox/flox Cnp1-Cre mice (Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h−/− mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h−/− mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult Fa2h−/− mice. The cerebellar deficits in 12-month-old Fa2hflox/flox Cnp1-Cre mice were indistinguishable from Fa2h−/−mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2hflox/flox Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h−/− mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.

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“…Interestingly, the level of upregulation was an order of magnitude greater compared to other myelin-associated genes Cgt and P 0 , suggesting that FA2H may have an additional function other than producing myelin lipids. A subsequent study of D6P2T schwannoma cells showed evidence for a role of FA2H in cell differentiation (Alderson and Hama, 2009). As Schwann cells, D6P2T cells respond to cAMP and show differentiated phenotypes, including withdrawal from the cell cycle and upregulation of myelin basic protein (Clark et al, 1998; Friessen et al, 1997).…”

Section: Hydroxy-ceramide In Cell Signalingmentioning

confidence: 99%

2′-Hydroxy ceramide in membrane homeostasis and cell signaling

Kota

Hama

2014

Advances in Biological Regulation

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Ceramide is a precursor of complex sphingolipids and also plays important roles in cell signaling. With the advances in lipid analytical technologies, the structural diversity of ceramide species have become evident, and the complexity of cellular metabolism and function associated with distinct ceramide species is beginning to be revealed. One of the common structural variations of ceramide is 2′-hydroxylation of the N-acyl chain. Fatty acid 2-hydroxylase (FA2H) is one of the enzymes that introduce the hydroxyl group during de novo synthesis of ceramide. FA2H is essential for the normal functioning of the nervous system, as evidenced by demyelinating disorder associated with FA2H mutations in humans and mice. Studies of Fa2h mutant mice indicate that lack of 2′-hydroxy galactosylceramide in the myelin membrane results in loss of long-term stability of myelin and eventual demyelination. FA2H also regulates differentiation of various cell types (epidermal keratinocytes, schwannoma cells, adipocytes). When provided exogenously, ceramide induces apoptosis in many cell types. Interestingly, the effective concentration of 2′-hydroxy ceramide that induces apoptosis is significantly lower compared to non-hydroxy ceramide, and cells die much more rapidly, suggesting that 2′-hydroxy ceramide can mediate proapoptotic signaling distinct from non-hydroxy ceramide. Collectively, current evidence clearly shows that 2′-hydroxy ceramide and 2′-hydroxy complex sphingolipids have unique functions in membrane homeostasis and cell signaling that could not be substituted by non-hydroxy counterparts.

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Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

Cited by 26 publications

References 37 publications

Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients

Mass Spectrometry-Based Quantitative Metabolomics Revealed a Distinct Lipid Profile in Breast Cancer Patients

Central nervous system dysfunction in a mouse model of Fa2h deficiency

2′-Hydroxy ceramide in membrane homeostasis and cell signaling

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