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Cited by 49Protein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancerSphingolipid Metabolism and Signaling

Effects of transformation with the v-src oncogene on inositol phosphate metabolism in rat-1 fibroblasts. D-myo-inositol 1,4,5,6-tetrakisphosphate is increased in v-src-transformed rat-1 fibroblasts and can be synthesized from D-myo-inositol 1,3,4-trisphosphate in cytosolic extracts

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Mattingly, R.R., Stephens, L.R., Irvine, R.F., Garrison, J.C.·1991·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(18)98597-2
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Abstract

Rat-1 fibroblasts transformed with the v-src oncogene show a 6-fold increase in the apparent amount of an inositol polyphosphate which has a high performance liquid chromatography (HPLC) elution characteristic of the D/L-myo-inositol 1,4,5,6-tetrakisphosphate enantiomeric pair (Johnson, R.M., Wasilenko, W.J., Mattingly, R.R., Weber, M.J., and Garrison, J.C. (1989) Science 246, 121-124). By chemical and enzymatic analysis, the structure of this compound produced in both normal and v-src-transformed rat-1 fibroblasts has been determined to be principally D-myoinositol 1,4,5,6-tetrakisphosphate (D-Ins(1,4,5,6)P4). Chronic stimulation with endothelin-1 in the presence of Li+ significantly increased the amount of D/L-Ins(1,4,5,6)P4 only in the v-src-transformed rat-1 cells, suggesting that production of this compound may be remotely coupled to long term agonist-induced phosphatidylinositol turnover. Further evidence for such a link is provided by the progressive loss of D-Ins(1,4,5,6)P4 from the normal cells deprived of serum stimulation. To define a possible synthetic pathway for D-Ins(1,4,5,6)P4, cytosolic extracts of normal and v-src-transformed cells were incubated with [3H]inositol polyphosphates, and the reaction products were identified by HPLC elution and chemical analysis. Although inositol 1,3,4-trisphosphate 6-kinase activity was prominent in extracts of both normal and transformed cells, only the cytosol from v-src-transformed cells ultimately formed measurable amounts of D-Ins(1,4,5,6)P4 from [3H]inositol 1,3,4-trisphosphate. Approximately 6% of 0.1 microM inositol 1,3,4-trisphosphate was converted to D-Ins(1,4,5,6)P4 during a 2-h incubation at 37 degrees C. Inositol pentakisphosphate was identified as a likely intermediate in this conversion, and extracts of both normal and transformed cells converted [3H]inositol 1,3,4,5,6-pentakisphosphate to D-Ins(1,4,5,6)P4. The synthetic pathway described is consistent with the long term regulation of D/L-Ins(1,4,5,6)P4 levels in rat-1 fibroblasts seen in response to src transformation, serum withdrawal, and chronic endothelin treatment, and identifies several new potential interactions between the pathways of inositol polyphosphate metabolism and those of src transformation.

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  • There is some evidence that both PTEN and InsP4 levels change with progression through the cell cycle.

    “However there is some evidence that both PTEN and InsP4 levels change with progression through the cell cycle45.”

    From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [45]

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Authors
Mattingly, R. R., Stephens, L. R., Irvine, R. F., & Garrison, J. C.
Affiliations
University of Virginia (US)
ORCID
Stephens, L.R.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1991-08
Volume
266
Issue
23
Pages
15144-15153
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(18)98597-2
OpenAlex
W1562922570
Cited by
49
References
39
Citations by year
2025: 1 · 2023: 1 · 2019: 1 · 2018: 2 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 3
FWCI
2.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (CA40042, P01CA040042)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
v-src oncogene, oncogenic transformation, inositol phosphate metabolism, phosphatidylinositol turnover, endothelin-1, lithium, serum deprivation, Rat-1 fibroblasts
MeSH terms
Animals, Cell Line, Cell Transformation, Neoplastic, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, Cytosol, Fibroblasts, Inositol Phosphates, Oxidation-Reduction, Phosphorylation, Oncogene Protein pp60(v-src), Genes, src, Rats

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