Enhanced Serine Palmitoyltransferase Expression in Proliferating Fibroblasts, Transformed Cell Lines, and Human Tumors

Carton, Jill M.; Uhlinger, David J.; Batheja, Ameesha; Derian, Claudia K.; Ho, George; Argenteri, Dennis; D’Andrea, Michael R.

doi:10.1177/002215540305100603

Cited by 15 publications

(16 citation statements)

References 42 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mass of four saturated long-chain ceramide species was proportionally increased, and mass of C18:0 and C18:1 saturated fatty acids was decreased, suggesting that failure to express CFTR has distinct effects on ceramide species composition, although exact mechanisms are currently not known. Increased long-chain saturated ceramides could also reflect altered membrane lipid requirements during rapid cell growth (9,14,31,32). Of note is that similar observations with regard to ceramide composition were made in human plasma from CF patients.…”

Section: Discussionmentioning

confidence: 79%

“…The major pathway of sphingolipid synthesis occurs through recycling of long-chain sphingoid bases that are derived from the catabolism of complex sphingolipids. In contrast, de novo synthesis is not as ubiquitous and is often found to be increased in cells with a high proliferation rate (14,15). Serinepalmitoyl transferase (SPT), found in the endoplasmic reticulum, is the rate-limiting enzyme of de novo synthesis.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

Hamai

Keyserman

Quittell³

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) that affect protein structure and channel function. CFTR, localized in the apical membrane within cholesterol and sphingomyelin rich regions, is an ABC transporter that functions as a chloride channel. Here, we report that expression of defective CFTR (#F508CFTR or decreased CFTR) in human lung epithelial cell lines increases sphingolipid synthesis and mass of sphinganine, sphingosine, four long-chain saturated ceramide species, C16 dihydroceramide, C22, C24, C26-ceramide, and sphingomyelin, and decreases mass of C18 and unsaturated C18:1 ceramide species. Decreased expression of CFTR is associated with increased expression of longchain base subunit 1 of serine-palmitoyl CoA, the rate-limiting enzyme of de novo sphingolipid synthesis and increased sphingolipid synthesis. Overexpression of #F508CFTR in bronchoalveolar cells that do not express CFTR increases sphingolipid synthesis and mass, whereas overexpression of wild-type CFTR, but not of an unrelated ABC transporter, ABCA7, decreases sphingolipid synthesis and mass. The data are consistent with a model in which CFTR functions within a feedback system that affects sphingolipid synthesis and in which increased sphingolipid synthesis could reflect a physiological response to sequestration of sphingolipids or altered membrane structure.-Hamai, H., F. Keyserman, L. M. Quittell, and T. S. Worgall. Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling.

show abstract

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

Hamai

Keyserman

Quittell³

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…The role of cellular trafficking remains poorly understood in lymphoblastic leukemia, but may contribute to relapse in sanctuary sites or protection against cytotoxic agents. 67,80 In the context of enhanced mobility and tissue compartment penetration, quiescent cells may not only escape S phasedependent cytotoxicity, but also may dynamically upregulate drug efflux transporters and other pathways that are necessary for survival. 40,81,82 Using standard light microscopy, IF can be easily identified in postdiagnostic bone marrow samples, but usually only after several weeks of treatment.…”

Section: Discussionmentioning

confidence: 99%

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Winter

Jiang²,

Khawaja

et al. 2007

Blood

View full text Add to dashboard Cite

The clinical and cytogenetic features associated with T-cell acute lymphoblastic leukemia (T-ALL) are not predictive of early treatment failure. Based on the hypothesis that microarrays might identify patients who fail therapy, we used the Affymetrix U133 Plus 2.0 chip and prediction analysis of microarrays (PAM) to profile 50 newly diagnosed patients who were treated in the Children's Oncology Group (COG) T-ALL Study 9404. We identified a 116-member genomic classifier that could accurately distinguish all 6 induction failure (IF) cases from 44 patients who achieved remission; network analyses suggest a prominent role for genes mediating cellular quiescence. Seven genes were similarly upregulated in both the genomic classifier for IF patients and T-ALL cell lines having acquired resistance to neoplastic agents, identifying potential target genes for further study in drug resistance. We tested whether our classifier could predict IF IntroductionAcute lymphoblastic leukemia (ALL) is the most common form of cancer among children and young adults. Approximately 15% of patients express cellular and molecular features that are unique to T-lineage acute lymphoblastic leukemia (T-ALL). [1][2][3][4] Through the use of increasingly dose-intensive therapy, combined with an improved understanding of leukemic pathogenesis, disease-free survival for children with ALL has improved over the past 3 decades. 5 However, when matched for NCI-designated clinical risk features of age, initial white blood cell count, and evidence of extramedullary disease, patients with T-ALL are at an increased risk of relapse compared with children treated for precursor B-lineage acute lymphoblastic leukemia (B-ALL). 6 In addition, unlike many of the genetic biomarkers observed in patients with precursor B-ALL, the recurring karyotypic aberrations identified in T-ALL do not consistently correlate with outcome on modern treatment schemas. 2,7,8 For these reasons, the identification of prognostically relevant karyotypic and clinicopathologic abnormalities in T-ALL has been difficult to elucidate. The recent identification of T-ALL risk groups, as defined by minimal residual disease (MRD) status, 6,9,10 activating NOTCH1 mutations, 11-13 and response to induction therapy, 6,14,15 can be used to stratify treatment approaches. Nevertheless, the mechanisms of drug resistance that result in persistent disease and early treatment failure remain poorly understood.Gene expression microarrays are spotted with thousands of 25mer oligonucleotides, which correspond to transcripts of known and hypothetical genes within the human genome. By using microarrays for class discovery in hematopoietic malignancies, it has been possible to identify novel pathways in malignant transformation, 16,17 explore heterogeneities among study populations, 18-21 and segregate patients into prognostically relevant subsets. 18,22 While numerous genes and genetic signatures predicting disease course have been identified for patients with acute myelogenous leukemia, precursor B-ALL, and...

show abstract

“…There is also evidence for SPT being present in other regions of the cell, such as focal adhesions(251) and the nucleus (and, interestingly, appearing to shift to the nucleus in proliferating cells). (252) In the endoplasmic reticulum, the active site appears to be oriented toward the cytoplasm, 253,254 as for the other enzymes of ceramide biosynthesis. (253) It is likely that SPT interacts with other regulatory proteins.…”

Section: Sphingolipid Metabolic Pathwaysmentioning

confidence: 99%

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

2011

View full text Add to dashboard Cite

Enhanced Serine Palmitoyltransferase Expression in Proliferating Fibroblasts, Transformed Cell Lines, and Human Tumors

Cited by 15 publications

References 42 publications

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling

Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Contact Info

Product

Resources

About