Cell‐specific effects of RAS oncogene and protein kinase C agonist TPA on P‐glycoprotein function

Stromskaya, T. P.; Grigorian, Irina A.; Ossovskaya, Valeria; Rybalkina, Ekaterina Yu.; Chumakov, Peter M.; Копнин, Б. П.

doi:10.1016/0014-5793(95)00662-s

Cited by 18 publications

(10 citation statements)

References 12 publications

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“…In either case the activation of P-gp via angiotensin II could occur via ras activation or alternatively via raf-1 and its interaction with the nuclear transcription factor AP-1 [53, 54]. This phenomenon could hypothetically have a defensive character, as P-gp has an important detoxifying role against highly cytotoxic prenylcysteine methyl esters generated in the catabolism of proteins of the G and ras families [36].…”

Section: P-gp and Kidneymentioning

confidence: 99%

P Glycoprotein: A New Mechanism to Control Drug-Induced Nephrotoxicity

Moral

Olmo

Aguilar

et al. 1998

Nephron Exp Nephrol

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The role of P glycoprotein (P-gp) in kidney is now being explored, and under physiological conditions, this protein is thought to be an excretory pump of cationic xenobiotics and metabolites. Functionally, two different types of P-gp have been described, but only the class I has been related to drug transport, and its overexpression confers the multidrug resistance phenotype in tumoral cells. It has been proposed that P-gp is involved in the energy-dependent transport of substrates through the cell membrane (toxic metabolites, toxins, nutrients, ions, peptides, etc.) – like a ‘hydrophobic molecule vacuum cleaner’. Several physiological functions have been attributed to P-gp: defense against xenobiotic aggression and transmembrane transport of prenylcysteine methyl esters, removing these cytotoxic metabolites from cells. A variety of substrates ranging from chemotherapeutics to steroid hormones, antibiotics, and calcium channel blockers can be transported by P-gp, suggesting the possible involvement of this protein in other unknown functions. Results from our group and others have suggested that overexpression of P-gp in renal tubular and mesangial cells prevents pharmacological nephrotoxicity by cyclosporin A (CsA). On the other hand CsA, a substrate of the pump, could act as a blocker in tubular cells by competitive inhibition. One relevant aspect in kidney is the possible relationship between P-gp and protein kinase C. Several reports suggest that protein kinase C may play a role in inducing the P-gp overexpression in cells under xenobiotic pressure, through activation of the ras oncoprotein family. This could be mediated directly by angiotensin II as a ras activator. This way, the detoxicant function of P-gp against products of the ras catabolism could mediate their accumulation when the ‘vacuum cleaner’ function is blocked by CsA or tacrolimus, contributing to the initial development of fibroblastic activation that leads to interstitial fibrosis associated with nephrotoxicity by these immunosuppressor drugs. In conclusion, P-gp expression could be an important component of a complex detoxifying system in kidney against xenobiotics or regulating the traffic of endogenous metabolites responsible for the susceptibility of subjects to the development of nephrotoxicity against different drugs.

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Section: P-gp and Kidneymentioning

confidence: 99%

P Glycoprotein: A New Mechanism to Control Drug-Induced Nephrotoxicity

Moral

Olmo

Aguilar

et al. 1998

Nephron Exp Nephrol

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“…A common approach is to stinmlate the Ras signaling cascade by introducing the activated oncogene (5,7,24,32,53,59). We present a detailed characterization of the NRK-52E cell line and NRK-52E cells transfected with the H-ras oncogene, producing two new cell lines.…”

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confidence: 99%

H-ras-transformed NRK-52E renal epithelial cells have altered growth, morphology, and cytoskeletal structure that correlates with renal cell carcinoma in vivo

Best

Tanzer

Phelps

et al. 1999

In Vitro Cell.Dev.Biol.-Animal

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We studied the effect of the ras oncogene on the growth kinetics, morphology, cytoskeletal structure, and tumorigenicity of the widely used NRK-52E rat kidney epithelial cell line and two H-ras oncogene-transformed cell lines, H/1.2-NRK-52E (H/1.2) and H/6.1-NRK-52E (H/6.1). Population doubling times of NRK-52E, H/1.2, and H/6.1 cells were 28, 26, and 24 h, respectively, with the transformed cells reaching higher saturation densities than the parent cells. NRK-52E cells had typical epithelial morphology with growth in colonies. H/1.2 and H/6.1 cell colonies were more closely packed, highly condensed, and had increased plasma membrane ruffling compared to parent cell colonies. NRK-52E cells showed microfilament, microtubule, and intermediate filament networks typical of epithelial cells, while H/1.2 and H/6.1 cells showed altered cytoskeleton architecture, with decreased stress fibers and increased microtubule and intermediate filament staining at the microtubule organizing center. H/1.2 and H/6.1 cells proliferated in an in vitro soft agar transformation assay, indicating anchorage-independence, and rapidly formed tumors in vivo with characteristics of renal cell carcinoma, including mixed populations of sarcomatoid, granular, and clear cells. H/6.1 cells consistently showed more extensive alterations of growth kinetics, morphology, and cytoskeleton than H/1.2 cells, and formed tumors of a more aggressive phenotype. These data suggest that analysis of renal cell characteristics in vitro may have potential in predicting tumor behavior in vivo, and significantly contribute to the utility of these cell lines as in vitro models for examining renal epithelial cell biology and the role of the ras proto-oncogene in signal transduction involving the cytoskeleton.

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“…For this purpose we analysed the sublines of Rat1 ®broblasts, rat IAR-2 epitheliocytes as well as murine p53-de®cient 10(3) ®broblasts bearing retroviral constructs with various p53 cDNAs and activated N-rasasp12 or v-mos oncogenes which were developed by us earlier Stromskaya et al, 1995). The method of computerassisted morphometry (Dunn and Brown, 1986) was used for assessment of cell morphology.…”

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confidence: 99%

“…We also observed disappearance of circumferential actin bundle and prominent straight actin bundles of micro®laments in the central regions of cells ( Figure 1b). (Montesano et al, 1975) derivatives expressing pPS/neo constructs with various human p53 cDNAs and/or pPS/hygro vector containing human activated N-ras ssp12 oncogene were obtained as a result of retrovirus-mediated gene transfer Stromskaya et al, 1995). The Rat/ mos cells bearing v-mos oncogene were isolated after Ca 2+ PM co-transfection of pRSV/mos vector along with pPs/hygro plasmid .…”

mentioning

confidence: 99%