Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1

Lucas, Luisa; Penalva, Verónica; Molina, Ana Ramı́rez de; Peso, Luis del; Lacal, Juan Carlos

doi:10.3892/ijo.21.3.477

Cited by 11 publications

(10 citation statements)

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“…Differential functioning of oncogenic mutants of other signaling molecules compared with the wild type form has been reported previously (54 -56). For example, oncogenic Ras constitutively activates phospholipase D by a protein kinase C-independent mechanism that is different from the protein kinase C-dependent mechanism used by wild type Ras (56). Instead, we have observed that GH-activated RhoA increases GH-stimulated, Stat5-mediated transcription by abrogation of p300/HDAC6 repression of Stat5-mediated transcription.…”

Section: Discussioncontrasting

confidence: 60%

RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription

Ling

Lobie

2004

Journal of Biological Chemistry

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We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoAdependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.

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Section: Discussioncontrasting

confidence: 60%

RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription

Ling

Lobie

2004

Journal of Biological Chemistry

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“…However, it is established that growth factor stimulation and Ras activation lead to modulation of phospholipid metabolism (54,55). More specifically, the PI3K pathway has been shown to participate in the activation of choline kinase as well as PLD (56,57). Thus, possible explanations for the decrease in phosphocholine that follows treatment with LY294002 and wortmannin could be (a) inhibition of choline kinase activity (which can also be achieved by U0126; ref.…”

Section: Discussionmentioning

confidence: 99%

“…This model suggests more experiments that can be carried out to elucidate further details on the effects of molecular therapeutics on phosphocholine and other metabolites, including the use of RNA interference to knockdown particular components of the pathways shown. With respect to this model, it is increasingly apparent that activation of more than one downstream Ras effector pathway (e.g., Raf-1 and RalGDS) is necessary for the upregulation of enzymes, such as choline kinase and PLD (56,57,63). Thus, abrogation of signaling via any one of the various effector pathways may well be sufficient for the effect on phosphocholine to become manifest as seen with the Raf-MEK-ERK1/2 pathway inhibitor U0126 (31).…”

Section: Discussionmentioning

confidence: 99%

Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells

Beloueche‐Babari

Jackson

Al-Saffar

et al. 2006

Molecular Cancer Therapeutics

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Phosphoinositide 3-kinase (PI3K) is an attractive target for novel mechanism-based anticancer treatment. We used magnetic resonance (MR) spectroscopy (MRS) to detect biomarkers of PI3K signaling inhibition in human breast cancer cells. MDA-MB-231, MCF-7, and Hs578T cells were treated with the prototype PI3K inhibitor LY294002, and the 31 P MR spectra of cell extracts were monitored. In every case, LY294002 treatment was associated with a significant decrease in phosphocholine levels by up to 2-fold (P < 0.05). In addition, a significant increase in glycerophosphocholine levels by up to 5-fold was also observed (P V 0.05), whereas the content of glycerophosphoethanolamine, when detectable, did not change significantly. Nucleotide triphosphate levels did not change significantly in MCF-7 and MDA-MB-231 cells but decreased by f1.3-fold in Hs578T cells (P = 0.01). The changes in phosphocholine and glycerophosphocholine levels seen in cell extracts were also detectable in the 31 P MR spectra of intact MDA-MB-231 cells following exposure to LY294002. When treated with another PI3K inhibitor, wortmannin, MDA-MB-231 cells also showed a significant decrease in phosphocholine content by f1.25-fold relative to the control (P < 0.05), whereas the levels of the remaining metabolites did not change significantly. Our results indicate that PI3K inhibition in human breast cancer cells by LY294002 and wortmannin is associated with a decrease in phosphocholine levels. [Mol Cancer Ther 2006;5(1):187 -96]

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“…Recent work has demonstrated the complex oncogenic regulation of PC-PLD with two positive regulatory pathways that are mediated by RALGDS and PI3K, and two negative feedback mechanisms that are mediated by RAF and RALGDS 71,98 . In turn, PC-PLD was identified as a regulator of cell transformation and tumour progression 71 .…”

Section: Oncogenic Regulation Of Choline Metabolismmentioning

confidence: 99%

Choline metabolism in malignant transformation

2011

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Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

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Modulation of phospholipase D by Ras proteins mediated by its effectors Ral-GDS, PI3K and Raf-1

Cited by 11 publications

References 0 publications

RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription

RhoA/ROCK Activation by Growth Hormone Abrogates p300/Histone Deacetylase 6 Repression of Stat5-mediated Transcription

Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells

Choline metabolism in malignant transformation

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