nach oben

Pediatric Nephrology

Erschienen in:

01.08.2011 | Original Article

Overexpression of p18^INK4C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis

verfasst von: Yi Zhang, Li Yuan, Lili Fu, Chunyan Liu, Dongmei Liu, Changlin Mei

Erschienen in: Pediatric Nephrology | Ausgabe 8/2011

Einloggen, um Zugang zu erhalten

Abstract

Studies have demonstrated that cyclin-dependent kinase inhibitors (CDKI) that inhibit cell-cycle progression have a protective effect against acute kidney injury (AKI). Most studies have focused on the CIP/KIP family members of CDKI; only a few have explored the role of INK4 family members in AKI. Because INK4 family members block the G1-S transition, we postulated that they should have protective effects against AKI. The most conserved INK4 member is p18, so we selected it to explore its effects on cisplatin-induced renal cell injury. We overexpressed p18 in renal tubular epithelial cells (LLC-PK1) by transient transfection and investigated its effects on the cell cycle and proliferation. After transfection, cell injury was induced by cisplatin (100 μM) incubation for 24 h in a standard medium. The effect of p18 was assayed by assessing cell necrosis and apoptosis in transfected cells. The endoplasmic reticulum stress (ERS) pathway was evaluated to interpret the possible mechanism of p18 action in cisplatin-induced renal cell injury. Overexpression of p18 arrested cell cycle progression in the G1 phase and inhibited proliferation. Compared with vehicle transfection, p18 overexpression did not affect cisplatin-induced necrosis, but it reduced the percentage of apoptotic cells significantly. The severity of ERS induced by cisplatin was also decreased by p18 overexpression. P18 protects against cisplatin-induced renal cell injury. The mechanism of p18 protection may lie in its effect on the cell death pathway.

Waikar SS, Liu KD, Chertow GM (2008) Diagnosis, epidemiology and outcomes of acute kidney injury. Clin J Am Soc Nephrol 3:844–861PubMed

Okusa MD (2002) The inflammatory cascade in acute ischemic renal failure. Nephron 90:133–138PubMed

Ramesh G, Reeves WB (2002) TNF-α mediates cytokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110:835–842PubMedPubMedCentral

Oh DJ, Dursun B, He Z, Lu L, Hoke TS, Ljubanovic D, Faubel S, Edelstein CL (2008) Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice. Am J Physiol Renal Physiol 294:F264–F271PubMed

Del Rio M, Imam A, DeLeon M, Gomez G, Mishra J, Ma Q, Parikh S, Devarajan P (2004) The death domain of kidney ankyrin interacts with Fas and promotes Fas-mediated cell death in renal epithelia. J Am Soc Nephrol 15:41–51PubMed

Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17:1503–1520PubMed

Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O'Donnell MP, Rabb H (2001) Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 108:1283–1290PubMedPubMedCentral

Jiang M, Pabla N, Murphy RF, Yang T, Yin XM, Degenhardt K, White E, Dong Z (2007) Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. J Biol Chem 282:2636–2645PubMed

Wei Q, Dong G, Yang T, Megyesi J, Price PM, Dong Z (2007) Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 293:F1282–F1291PubMedPubMedCentral

10.

Cummings BS, Schnellmann RG (2002) Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 302:8–17PubMed

11.

Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 16:3–11PubMed

12.

Periyasamy-Thandavan S, Jiang M, Wei Q, Smith R, Yin XM, Dong Z (2008) Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int 74:631–640PubMed

13.

Shankland SJ, Wolf G (2000) Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol 278:F515–F529PubMed

14.

Morgan DO (1995) Principles of CDK regulation. Nature 374:131–134PubMed

15.

Peter M, Herskowitz I (1994) Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell 79:181–184PubMed

16.

Weinert T (1998) DNA damage and checkpoint pathways: molecular anatomy and interactions with repair. Cell 94:555–558PubMed

17.

Price PM, Safirstein RL, Megyesi J (2009) The cell cycle and acute kidney injury. Kidney Int 76:604–613PubMedPubMedCentral

18.

Megyesi J, Safirstein RL, Price PM (1998) Induction of p21^{WAF1/CIP1/SDI1} in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest 101:777–782PubMedPubMedCentral

19.

Nowak G, Price PM, Schnellmann RG (2003) Lack of a functional p21^WAF1/CIP1 gene accelerates caspase-independent apoptosis induced by cisplatin in renal cells. Am J Physiol Renal Physiol 285:F440–F450PubMed

20.

Yu F, Megyesi J, Safirstein RL, Price PM (2005) Identification of the functional domain of p21^(WAF1/CIP1) that protects cells from cisplatin cytotoxicity. Am J Physiol Renal Physiol 289:F514–F520PubMed

21.

Megyesi J, Andrade L, Vieira JM Jr, Safirstein RL, Price PM (2002) Coordination of the cell cycle is an important determinant of the syndrome of acute renal failure. Am J Physiol Renal Physiol 283:F810–F816PubMed

22.

Price PM, Yu F, Kaldis P, Aleem E, Nowak G, Safirstein RL, Megyesi J (2006) Dependence of cisplatin-induced cell death in vitro and in vivo on cyclin-dependent kinase 2. J Am Soc Nephrol 17:2434–2442PubMedPubMedCentral

23.

Yu F, Megyesi J, Price PM (2008) Cytoplasmic initiation of cisplatin cytotoxicity. Am J Physiol Renal Physiol 295:F44–F452PubMedPubMedCentral

24.

Price PM, Safirstein RL, Megyesi J (2004) Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol 286:F378–F384PubMed

25.

Hengst L, Reed SI (1998) Inhibitors of the Cip/Kip family. Curr Top Microbiol Immunol 227:25–41PubMed

26.

Sherr CJ, Roberts JM (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 9:1149–1163PubMed

27.

Cordon-Cardo C (1995) Mutation of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol 147:545–560PubMedPubMedCentral

28.

Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, Ogara MF (2007) INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 59:419–426PubMed

29.

Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O’Keefe CL, Matera AG, Xiong Y (1994) Growth suppression by p18, a p16^INK4/MTS1- and p14^INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8:2939–2952PubMed

30.

Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ (1995) Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 15:2672–2681PubMedPubMedCentral

31.

Choi KS, Eom YW, Kang Y, Ha MJ, Rhee H, Yoon JW, Kim SJ (1999) Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger apoptosis through the phosphorylation of retinoblastoma protein in FaO hepatoma cells. J Biol Chem 274:31775–31783PubMed

32.

Wang D, Lippard SJ (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4:307–320PubMed

33.

Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279PubMed

34.

Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007PubMed

35.

Lieberthal W, Triaca V, Levine J (1996) Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol 270:F700–F708PubMed

36.

Razzaque MS, Koji T, Kumatori A, Taguchi T (1999) Cisplatin-induced apoptosis in human proximal tubular epithelial cells is associated with the activation of the Fas/Fas ligand system. Histochem Cell Biol 111:359–365PubMed

37.

Seth R, Yang C, Kaushal V, Shah SV, Kaushal GP (2005) p53-dependent caspase-2 activiation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury. J Biol Chem 280:31230–31239PubMed

38.

Park MS, De Leon M, Devarajan P (2002) Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol 13:858–865PubMed

39.

Huang Q, Dunn RT 2nd, Jayadev S, DiSorbo O, Pack FD, Farr SB, Stoll RE, Blanchard KT (2001) Assessment of cisplatin-induced nephrotoxicity by microarray technology. Toxicol Sci 63:196–207PubMed

40.

Muruganandan S, Cribb AE (2006) Calpain-induced endoplasmic reticulum stress and cell death following cytotoxic damage to renal cells. Toxicol Sci 94:118–128PubMed

41.

Cribb AE, Peyrou M, Muruganandan S, Schneider L (2005) The endoplasmic reticulum in xenobiotic toxicity. Drug Metab Rev 37:405–442PubMed

42.

Peyrou M, Hanna PE, Cribb AE (2007) Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. Toxicol Sci 99:346–353PubMed

43.

Liu H, Baliga R (2005) Endoplasmic reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis. J Am Soc Nephrol 16:1985–1992PubMed

44.

Bernales S, Papa FR, Walter P (2006) Intracellular signaling by the unfolded protein response. Annu Rev Cell Dev Biol 22:487–508PubMed

45.

Lin JH, Walter P, Yen TS (2008) Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 3:399–425PubMedPubMedCentral

46.

Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731PubMedPubMedCentral

47.

Mori K (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101:451–454PubMed

48.

Kleizen B, Braakman I (2004) Protein folding and quality control in the endoplasmic reticulum. Curr Opin Cell Biol 16:343–349PubMed

49.

Zhang K, Kaufman RJ (2006) The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66:S102–S109PubMed

50.

Marciniak SJ, Ron D (2006) Endoplasmic reticulum stress signaling in disease. Physiol Rev 86:1133–1149PubMed

51.

Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885PubMedPubMedCentral

52.

Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase 12 mediates ER-specific apoptosis and cytotoxicity by amyloid-β. Nature 403:98–103PubMed

53.

Kalai M, Lamkanfi M, Denecker G, Boogmans M, Lippens S, Meeus A, Declercq W, Vandenabeele P (2003) Regulation of the expression and processing of caspase 12. J Cell Biol 162:457–467PubMedPubMedCentral

54.

Oyadomari S, Mori M (2004) Role of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMed

55.

Kondo S, Barna BP, Kondo Y, Tanaka Y, Casey G, Liu J, Morimura T, Kaakaji R, Peterson JW, Werbel B, Barnett GH (1996) WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. Oncogene 13:1279–1285PubMed

56.

Lincet H, Poulain L, Remy JS, Deslandes E, Duigou F, Gauduchon P, Staedel C (2000) The p21^(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett 161:17–26PubMed

57.

Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen-Kiang S, Su L, Xiong Y (1998) CDK inhibitors p18^INK4c and p27^Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12:2899–2911PubMedPubMedCentral

58.

Al-Mohanna MA, Manogaran PS, Al-Mukhalafi Z, A Al-Hussein K, Aboussekhra A (2004) The tumor suppressor p16^(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Oncogene 23:201–212PubMed

59.

Le HV, Minn AJ, Massagué J (2005) Cyclin-dependent kinase inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells. J Biol Chem 280:32018–32025PubMed

60.

Scassa ME, Marazita MC, Ceruti JM, Carcagno AL, Sirkin PF, González-Cid M, Pignataro OP, Cánepa ET (2007) Cell cycle inhibitor, p19^INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair. DNA Repair 6:626–638PubMed

61.

Tavera-Mendoza LE, Wang TT, White JH (2006) p19^INK4D and cell death. Cell Cycle 5:596–598PubMed

62.

Massagué J (2004) G1 cell-cycle control and cancer. Nature 432:298–306PubMed

63.

Trimarchi JM, Lees JA (2002) Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 3:11–20PubMed

Titel: Overexpression of p18INK4C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis
verfasst von: Yi Zhang
Li Yuan
Lili Fu
Chunyan Liu
Dongmei Liu
Changlin Mei
Publikationsdatum: 01.08.2011
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 8/2011
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-011-1877-y

Update Pädiatrie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Overexpression of p18^INK4C in LLC-PK1 cells increases resistance to cisplatin-induced apoptosis

Abstract

Neu im Fachgebiet Pädiatrie

Neuer Typ-1-Diabetes bei Kindern am Wochenende eher übersehen

Neue Studienergebnisse zur Myopiekontrolle mit Atropin

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Update Pädiatrie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2011

Urinary MMP-9/NGAL complex in children with acute cystitis

Pulse wave velocity, blood pressure and bicycle tyres

Effect of diet, enalapril, or losartan in post-diarrheal hemolytic uremic syndrome nephropathy

Renal amyloidosis in children

Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature

Hepatoblastoma and prune belly syndrome: a potential association

Neu im Fachgebiet Pädiatrie

Neuer Typ-1-Diabetes bei Kindern am Wochenende eher übersehen

Neue Studienergebnisse zur Myopiekontrolle mit Atropin

Spinale Muskelatrophie: Neugeborenen-Screening lohnt sich

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

Update Pädiatrie