Regulation of Ras Proteins and Their Involvement in Signal-Transduction Pathways (Review)

Lacal, JC; Carnero, Amancio

doi:10.3892/or.1.4.677

Cited by 15 publications

(23 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ChoK inhibitors that interfere with ChoK function but have no e ect on PLD, also show antiproliferative and antitumoral actions (HernaÂ ndez-Alcoceba et al, 1997. Alterations in the balance of the pathways regulating the generation of mitogenic (PCho) and structural signals (PC) may be critical for the integrity of the cells (Lacal and Carnero, 1994;Lacal, 1997). PLD activation and/or desensitization by HePC would alter the balance of choline-PCho with drastic consequences, connecting the apoptotic program.…”

Section: Discussionmentioning

confidence: 99%

“…Phorbol esters and growth factors like platelet-derived growth factor (PDGF) activate PLD by a PKC-dependent pathway (Lacal and Carnero, 1994;Lacal, 1997;del Peso et al, 1996del Peso et al, , 1997. On the other hand, oncogenes such as ras activate PLD by a mechanism independent of PKC that may involve the GTPase Ral, a member of the Ras superfamily (Lacal and Carnero, 1994;Lacal, 1997;Carnero et al, 1994a, b;Carnero and Lacal, 1995;del Peso et al, 1996del Peso et al, , 1997Jiang et al, 1995). Finally, other small GTPases of the Ras superfamily, such as ARF and members of the Rho family can directly interact and activate PLD (Han et al, 1998;Exton, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Among these, cell proliferation, transformation and apoptosis, have been extensively studied (Majerus et al, 1986;Berridge, 1993;Lacal and Carnero, 1994;Lacal, 1997). One of the key enzymes in these processes is Phospholipase D (PLD), that catalyses the hydrolysis of phosphatidylcholine (PC) to generate both choline (Cho) and phosphatidic acid (PA).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Lucas¹,

Hernández-Alcoceba

Penalva³

et al. 2001

Oncogene

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Lucas¹,

Hernández-Alcoceba

Penalva³

et al. 2001

Oncogene

View full text Add to dashboard Cite

“…In addition to the well-known activation of the Raf/MAPK pathways, phospholipid metabolism is also regulated by Ras proteins (Lacal and Carnero, 1994). At least four important enzymes involved in phospholipid metabolism are activated by ras oncogenes, two phospholipases: PLA 2 (Bar Sagi and Feramisco, 1986;Carnero et al, 1994a) and PLD (Carnero et al, 1994a,b;Carnero and Lacal, 1995), and two kinases: PI3K (RodrõÂ guez Viciana et al, 1994) and ChoK (Lacal et al, 1987;Macara, 1989;Lacal, 1990;Teegarden et al, 1990;Cuadrado et al, 1993Cuadrado et al, , 1994aJimeÂ nez et al, 1995;Ratnam and Kent, 1995).…”

Section: Antiproliferative E Ects Of Hc-3 Derivatives On Oncogenes-trmentioning

confidence: 99%

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Saniger²,

et al. 1997

View full text Add to dashboard Cite

Recent progress in deciphering the molecular basis of carcinogenesis is of utmost importance to the development of new anticancer strategies. To this end, it is essential to understand the regulation of both normal cell proliferation and its alterations in cancer cells. We have previously demonstrated that in ras-transformed cells there is an increased level of phosphorylcholine (PCho) resulting from a constitutive activation on choiline kinase (ChoK). The importance of ChoK for the regulation of cell proliferation has also been proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically reduces entry into the S phase after stimulation with growth factors. Here we report the synthesis of several new compounds which are highly speci®c inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory activity, compared to HC-3 under ex vivo or in vitro conditions respectively. These novel compounds also drastically reduce entry into the S phase after stimulation with speci®c growth factors. A more profound inhibition of cell proliferation was observed in ras-, src-and mos-transformed cells in the presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3 cells. By contrast, this e ect was not observed in fos-transformed cells. While ras, src and mos transformation is associated with elevated levels of ChoK activity, fos-induced transformation does not a ect ChoK activity. The inhibitory e ect on proliferation of the new compounds correlates with their ability to inhibit the production of phosphorylcholine in whole cells, a proposed novel second messenger for cell proliferation. These results strongly support a critical role of choline kinase in the regulation of cell growth and makes this enzyme a novel target for the design of new antiproliferative and anticancer drugs.

show abstract

“…It is well established that one characteristic of transformed cells is perturbation of lipid synthetic and degradative pathways (71)(72)(73), suggesting an active role of lipids in oncogenic transformation. Expression of oncogenic Ras correlates with increased levels of phosphocholine and phosphoethanolamine (45,(73)(74)(75), diacylglycerols (76), inositol phosphates (77), and arachidonic acid (78). The stimulated degradation of phospholipids is accompanied by an increased biosynthesis (45,(73)(74)(75), demonstrating an accelerated turnover of lipids in transformed cells.…”

Section: Transient Expression Of Sp3 Increases the Amount Of Both Ct␣mentioning

confidence: 99%

Oncogenic Ha-Ras Transformation Modulates the Transcription of the CTP:Phosphocholine Cytidylyltransferase α Gene via p42/44MAPK and Transcription Factor Sp3

Bakovic¹,

Waite²,

Vance

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Phosphatidylcholine (PC)1 is the most abundant phospholipid in mammalian cellular membranes. Besides having a structural role in membranes and lipoproteins (1-3), PC plays an important role in signal transduction as a source of lipid second messengers (1-3). In all nucleated cells, PC is made primarily through the CDP-choline pathway in which the key enzyme is CTP:phosphocholine cytidylyltransferase (CT) (2-6).Two genes that encode CT activity have been identified and characterized. CT␣ is expressed in many cells and tissues (7-13) and has a predicted structure that contains catalytic, phosphorylation, and lipid binding domains as well as a nuclear localization sequence (8, 14 -21). Recently, CT␤ has been identified in human tissues and appears to exist as two splice variants, CT␤1 and CT␤2, differing at their C termini (22, 23). Like CT␣, CT␤1/2 contains catalytic and lipid binding domains. However, CT␤1 lacks the phosphorylation domain, and both CT␤1 and CT␤2 lack the nuclear localization sequence (23).In the last several years, studies have shown that CT can be regulated at both the transcriptional level and post-transcriptionally. CT mRNA is increased after partial hepatectomy in rats (13), after stimulation with colony-stimulating factor 1 in macrophages (24), and during development and growth (25)(26)(27)(28). It remains to be determined whether these increases in the message levels are the result of CT␣ and/or CT␤1/2 mRNA stability, an increase in gene transcription, or a combination of both.The murine CT␣ gene (Ctpct) was cloned and characterized by Tang and co-workers (29). The Ctpct promoter contains several putative elements for binding transcription factors, including Ap1, an overlapping site for nuclear factor-B, E2F, and Elk1, one sterol response element, as well as three elements for Sp-related factors (30). We have shown that Sp1, Sp2, and Sp3 bind competitively to three GC-rich elements and that relative promoter activity depends upon the abundance of these factors (31). We further established that transcription enhancer factor-4 can bind to an upstream regulatory element (Ϫ103/Ϫ82) and enhance the CT␣ gene expression through its interactions with the basal transcriptional machinery (32). In agreement with the finding that lipoprotein deficiency induces the expression of CT␣ mRNA and protein in alveolar type II epithelial cells (33), and our observation that the CT␣ promoter contains a putative sterol response element (30), studies by Kast et al. (34) indicate a role for cholesterol/sterol response element-binding protein and the functionality of the sterol response element in the regulation of CT␣ gene expression in Chinese hamster ovary cells and THP-1 cells. On the other hand, Lagace et al. (35) have shown that cholesterol/sterol response element-binding protein can stimulate PC biosynthe-

show abstract

Regulation of Ras Proteins and Their Involvement in Signal-Transduction Pathways (Review)

Cited by 15 publications

References 0 publications

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Modulation of phospholipase D by hexadecylphosphorylcholine: a putative novel mechanism for its antitumoral activity

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Oncogenic Ha-Ras Transformation Modulates the Transcription of the CTP:Phosphocholine Cytidylyltransferase α Gene via p42/44MAPK and Transcription Factor Sp3

Contact Info

Product

Resources

About