FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2095284584> ?p ?o ?g. }

• W2095284584 endingPage "F513" @default.
• W2095284584 startingPage "F512" @default.
• W2095284584 abstract "EDITORIAL FOCUSProvenance of the protective property of p21Karl A. NathKarl A. NathPublished Online:01 Sep 2005https://doi.org/10.1152/ajprenal.00224.2005MoreSectionsPDF (38 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat in the current issue ofAmerican Journal of Physiology-Renal Physiology, the study by Yu et al. (26) significantly advances an important line of investigation initiated by these investigators in 1996 (17) and which steadfastly interrogated the functional significance of the induction of p21WAF1/CIP1/SDI1 (p21) in the acutely injured kidney (13–18, 22, 26). p21 Is a member of the Cip/Kip family of proteins, which promote cell cycle arrest by binding to and inhibiting cyclin-dependent kinases (cdk), the latter, when coupled with specific cyclins, facilitates the orderly procession of the cell cycle (21, 24). It was initially observed that in response to diverse acute insults, prompt and prominent upregulation of p21 occurred in the kidney (17), a finding that led these investigators to question why a cell cycle inhibitor would be strongly expressed in a disease process that obligates cell proliferation in the recovery program that nurses the kidney back to normalcy. Was this induction of p21 maladaptive and inimical, adaptive and salutary, or quite simply, a functionally inert and unengaged epiphenomenon?An answer was provided in subsequent studies in p21 null mutant mice (13, 16): the induction of p21 was clearly beneficial to the acutely stressed kidney as indicated by the heightened structural and functional impairment of the kidney when p21−/− mice were subjected to a nephrotoxin such as cisplatin or to acute renal ischemia (13, 16). To explain the basis for the protective effects of p21 induced in the kidney following exposure to cisplatin, these authors suggested that the inhibitory effect of p21 on the cell cycle would proscribe cells with damaged DNA from progressing through the cell cycle, thereby forestalling the cellular demise that would otherwise occur (16). While this thesis was entirely consistent with the understanding of the biology of p21 that existed at the time, it became increasingly apparent that the raison d'être of p21 extended way beyond its restraining effect on the cell cycle, that the function of p21 was multifaceted, and that its nature was nuanced (4, 5, 7, 8, 10, 19, 21, 24, 25). For example, evidence was accrued that p21 influenced transcriptional programs, signaling pathways, and other mechanisms that broadly determine cell fate and phenotype; notably, p21 influenced cell survival, commonly preventing apoptosis on the one hand, but on the other, and quite uncommonly, fostering apoptosis (4, 5, 7, 8, 19, 25). The antiapoptotic effects of p21 seemed distinct from its inhibitory effects on the cell cycle and emanated from cytoplasmic rather than nuclear expression of the protein (3). Finally, in contrast to its impressive protective effects in acute renal injury, the induction of p21 appeared maladaptive in chronic renal injury attended by enhanced renal hypertrophy, as occurs in models of remnant kidney injury and diabetic nephropathy (1, 15).The functional effect of p21 in cisplatin-induced toxicity in renal epithelial cells was probed by Megyesi, Price, and Safirstein and collaborators (14, 18, 22) in a series of studies that produced clear and consistent conclusions: cells deficient in p21, when exposed to cisplatin, exhibited decreased survival and increased apoptosis, and conversely, overexpression of p21 by adenoviral vectors markedly reduced cisplatin-induced cell death. Moreover, the beneficial effects of p21 appeared independent of an action on the cell cycle and were channeled through caspase-dependent and caspase-independent processes (22).These findings, in turn, led to the issue of the basis of such cytoprotective effects of p21. Several possibilities existed, as p21 possesses numerous domains that facilitate binding to proteins relevant to cell survival, including binding domains for procaspase-3, ASK1, c-Myc, GADD45, and calmodulin; indeed, antagonism of some of these proteins has been incriminated as the basis for the survival effects of p21 (3–45, 7, 19, 25). The present findings of Yu et al. (26), however, demonstrate that the antiapoptotic effects of p21 originate from the domain that binds cdk2, one of the major targets inhibited by p21 as it arrests the cell cycle. These intriguing findings may seem initially surprising, because cdk2 is a critical contributor to the progression of the cell cycle and yet the antiapoptotic effects of p21 are considered independent of its inhibition of the cell cycle. Concordance of these considerations is readily apparent when one recognizes the compartment-specific effects of cdk2 (4, 8, 9, 11). Cyclin/cdk complexes easily commute between the nuclear and cytoplasmic compartments (4, 8, 11), and once within the cytoplasm, and as shown by Shankland and collaborators (9) in mesangial cells, these complexes exert far different effects on cell fate; in contrast to the proliferative effects of these complexes in the nucleus, cytoplasmic localization of these complexes may trigger apoptosis (4, 8, 9, 11).Besides elucidating the origins of the antiapoptotic actions of p21, this study uncovered new and therapeutically exciting insights regarding the pathogenesis of cisplatin-induced nephrotoxicity, an adverse effect that may significantly limit the utility of a highly effective chemotherapeutic agent (2) and one that is the focus of substantial investigation (12, 20, 23). It would be of considerable interest if cdk2 activity contributes to the nephrotoxicity of cisplatin in vivo because inhibiting this activity may mitigate such toxicity, the clinical feasibility of which is aided by the current clinical evaluation of several cdk inhibitors as chemotherapeutic agents (6).In summary, the study by Yu et al. (26) uncovers the provenance of the protective effects of p21 against cisplatin-induced cytotoxicity, and in the process, discovers a novel mechanism that may underlie such toxicity. It thus represents an illuminating continuation of an important investigative path begun by this laboratory a decade ago which, along the way, led to novel biological insights regarding p21 and which now approaches a potential therapeutic stratagem for reducing the risk of cisplatin-induced nephrotoxicity.REFERENCES1 Al-Douahji M, Brugarolas J, Brown PA, Stehman-Breen CO, Alpers CE, and Shankland SJ. The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Kidney Int 56: 1691–1699, 1999.Crossref | PubMed | ISI | Google Scholar2 Arany I and Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol 23: 460–464, 2003.Crossref | PubMed | ISI | Google Scholar3 Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K, and Mizutani S. Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J 18: 1223–1234, 1999.Crossref | PubMed | ISI | Google Scholar4 Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13: 65–70, 2003.Crossref | PubMed | ISI | Google Scholar5 Dotto GP. p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 1471: M43–M56, 2000.PubMed | ISI | Google Scholar6 Fischer PM and Gianella-Borradori A. Recent progress in the discovery and development of cyclin-dependent kinase inhibitors. Expert Opin Invest Drugs 14: 457–477, 2005.Crossref | PubMed | ISI | Google Scholar7 Gartel AL and Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1: 639–649, 2002.PubMed | ISI | Google Scholar8 Golsteyn RM. Cdk1 and Cdk2 complexes (cyclin dependent kinases) in apoptosis: a role beyond the cell cycle. Cancer Lett 217: 129–138, 2005.Crossref | PubMed | ISI | Google Scholar9 Hiromura K, Pippin JW, Blonski MJ, Roberts JM, and Shankland SJ. The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene 21: 1750–1758, 2002.Crossref | PubMed | ISI | Google Scholar10 Inguaggiato P, Gonzalez-Michaca L, Croatt AJ, Haggard JJ, Alam J, and Nath KA. Cellular overexpression of heme oxygenase-1 up-regulates p21 and confers resistance to apoptosis. Kidney Int 60: 2181–2191, 2001.Crossref | PubMed | ISI | Google Scholar11 Jackman M, Kubota Y, den Elzen N, Hagting A, and Pines J. Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm. Mol Biol Cell 13: 1030–1045, 2002.Crossref | PubMed | ISI | Google Scholar12 Kaushal GP, Kaushal V, Hong X, and Shah SV. Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells. Kidney Int 60: 1726–1736, 2001.Crossref | PubMed | ISI | Google Scholar13 Megyesi J, Andrade L, Vieira JM Jr, Safirstein RL, and Price PM. Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure. Kidney Int 60: 2164–2172, 2001.Crossref | PubMed | ISI | Google Scholar14 Megyesi J, Andrade L, Vieira JM Jr, Safirstein RL, and Price PM. Coordination of the cell cycle is an important determinant of the syndrome of acute renal failure. Am J Physiol Renal Physiol 283: F810–F816, 2002.Link | ISI | Google Scholar15 Megyesi J, Price PM, Tamayo E, and Safirstein RL. The lack of a functional p21(WAF1/CIP1) gene ameliorates progression to chronic renal failure. Proc Natl Acad Sci USA 96: 10830–10835, 1999.Crossref | PubMed | ISI | Google Scholar16 Megyesi J, Safirstein RL, and Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest 101: 777–782, 1998.Crossref | PubMed | ISI | Google Scholar17 Megyesi J, Udvarhelyi N, Safirstein RL, and Price PM. The p53-independent activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal failure. Am J Physiol Renal Fluid Electrolyte Physiol 271: F1211–F1216, 1996.Link | ISI | Google Scholar18 Nowak G, Price PM, and Schnellmann RG. Lack of a functional p21WAF1/CIP1 gene accelerates caspase-independent apoptosis induced by cisplatin in renal cells. Am J Physiol Renal Physiol 285: F440–F450, 2003.Link | ISI | Google Scholar19 O'Reilly MA. Redox activation of p21Cip1/WAF1/Sdi1: a multifunctional regulator of cell survival and death. Antioxid Redox Signal 7: 108–118, 2005.Crossref | PubMed | ISI | Google Scholar20 Portilla D. Energy metabolism and cytotoxicity. Semin Nephrol 23: 432–438, 2003.Crossref | PubMed | ISI | Google Scholar21 Price PM, Megyesi J, and Safirstein RL. Cell cycle regulation: repair and regeneration in acute renal failure. Semin Nephrol 23: 449–459, 2003.Crossref | PubMed | ISI | Google Scholar22 Price PM, Safirstein RL, and Megyesi J. Protection of renal cells from cisplatin toxicity by cell cycle inhibitors. Am J Physiol Renal Physiol 286: F378–F384, 2004.Link | ISI | Google Scholar23 Ramesh G and Reeves WB. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110: 835–842, 2002.Crossref | PubMed | ISI | Google Scholar24 Shankland SJ and Wolf G. Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol 278: F515–F529, 2000.Link | ISI | Google Scholar25 Weinberg WC and Denning MF. P21Waf1 control of epithelial cell cycle and cell fate. Crit Rev Oral Biol Med 13: 453–464, 2002.Crossref | PubMed | Google Scholar26 Yu F, Megyesi J, Safirstein RL, and Price PM. Identification of the functional domain of p21WAF1/CIP1 that protects cells from cisplatin cytotoxicity. Am J Physiol Renal Physiol 289: F514–F520, 2005.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: K. A. Nath, Mayo Clinic College of Medicine, 200 First St., SW, Rochester, MN 55905 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByThymoquinone and geraniol alleviate cisplatin-induced neurotoxicity in rats through downregulating the p38 MAPK/STAT-1 pathway and oxidative stressLife Sciences, Vol. 228Acute kidney injury induces dramatic p21 upregulation via a novel, glucocorticoid-activated, pathwayRichard A. Zager* and Ali C. M. Johnson*25 March 2019 | American Journal of Physiology-Renal Physiology, Vol. 316, No. 4Plasma and urinary p21: potential biomarkers of AKI and renal agingAli C. Johnson and Richard A. Zager22 October 2018 | American Journal of Physiology-Renal Physiology, Vol. 315, No. 5The deficiency of CX3CL1/CX3CR1 system ameliorates high fructose diet-induced kidney injury by regulating NF-κB pathways in CX3CR1-knock out mice16 March 2018 | International Journal of Molecular MedicineInvestigating the Process of Renal Epithelial Repair to Develop New TherapiesCyclin-dependent kinase inhibitor p18INK4c is involved in protective roles of heme oxygenase-1 in cisplatin-induced acute kidney injury1 July 2014 | International Journal of Molecular Medicine, Vol. 34, No. 3Deletion of p18INK4c aggravates cisplatin-induced acute kidney injury4 April 2014 | International Journal of Molecular Medicine, Vol. 33, No. 6CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injuryDerek P. DiRocco, John Bisi, Patrick Roberts, Jay Strum, Kwok-Kin Wong, Norman Sharpless, and Benjamin D. Humphreys15 February 2014 | American Journal of Physiology-Renal Physiology, Vol. 306, No. 42-Hydroxyestradiol slows progression of experimental polycystic kidney diseaseSharon Anderson, Terry T. Oyama, Jessie N. Lindsley, William E. Schutzer, Douglas R. Beard, Vincent H. Gattone, and Radko Komers1 March 2012 | American Journal of Physiology-Renal Physiology, Vol. 302, No. 5Uremia induces proximal tubular cytoresistance and heme oxygenase-1 expression in the absence of acute kidney injuryRichard A. Zager1 February 2009 | American Journal of Physiology-Renal Physiology, Vol. 296, No. 2The impact of aging on kidney repairRoland Schmitt, and Lloyd G. Cantley1 June 2008 | American Journal of Physiology-Renal Physiology, Vol. 294, No. 6Up-regulation of apoptosis and regeneration genes in the dorsal root ganglia during cisplatin treatmentExperimental Neurology, Vol. 210, No. 2Antitumor activity of a novel bis-aziridinylnaphthoquinone (AZ4) mediating cell cycle arrest and apoptosis in non-small cell lung cancer cell line NCI-H460Acta Pharmacologica Sinica, Vol. 28, No. 4Heme oxygenase-1: A provenance for cytoprotective pathways in the kidney and other tissuesKidney International, Vol. 70, No. 3 More from this issue > Volume 289Issue 3September 2005Pages F512-F513 Copyright & PermissionsCopyright © 2005 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00224.2005PubMed16093427History Published online 1 September 2005 Published in print 1 September 2005 Metrics Downloaded 132 times" @default.
• W2095284584 created "2016-06-24" @default.
• W2095284584 creator A5034141505 @default.
• W2095284584 date "2005-09-01" @default.
• W2095284584 modified "2023-10-18" @default.
• W2095284584 title "Provenance of the protective property of p21" @default.
• W2095284584 cites W1972305847 @default.
• W2095284584 cites W1972748173 @default.
• W2095284584 cites W1973959559 @default.
• W2095284584 cites W1976912787 @default.
• W2095284584 cites W1998263653 @default.
• W2095284584 cites W2002235730 @default.
• W2095284584 cites W2004809264 @default.
• W2095284584 cites W2019316722 @default.
• W2095284584 cites W2020621201 @default.
• W2095284584 cites W2060734153 @default.
• W2095284584 cites W2078252982 @default.
• W2095284584 cites W2088178433 @default.
• W2095284584 cites W2092557822 @default.
• W2095284584 cites W2118100544 @default.
• W2095284584 cites W2123408027 @default.
• W2095284584 cites W2130270207 @default.
• W2095284584 cites W2133718188 @default.
• W2095284584 cites W2148607448 @default.
• W2095284584 cites W2152522832 @default.
• W2095284584 cites W2155956189 @default.
• W2095284584 cites W2160099505 @default.
• W2095284584 cites W2316464883 @default.
• W2095284584 cites W2415462524 @default.
• W2095284584 cites W4240717991 @default.
• W2095284584 cites W4250210754 @default.
• W2095284584 doi "https://doi.org/10.1152/ajprenal.00224.2005" @default.
• W2095284584 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16093427" @default.
• W2095284584 hasPublicationYear "2005" @default.
• W2095284584 type Work @default.
• W2095284584 sameAs 2095284584 @default.
• W2095284584 citedByCount "20" @default.
• W2095284584 countsByYear W20952845842012 @default.
• W2095284584 countsByYear W20952845842014 @default.
• W2095284584 countsByYear W20952845842016 @default.
• W2095284584 countsByYear W20952845842018 @default.
• W2095284584 countsByYear W20952845842019 @default.
• W2095284584 crossrefType "journal-article" @default.
• W2095284584 hasAuthorship W2095284584A5034141505 @default.
• W2095284584 hasConcept C111472728 @default.
• W2095284584 hasConcept C121332964 @default.
• W2095284584 hasConcept C127313418 @default.
• W2095284584 hasConcept C138885662 @default.
• W2095284584 hasConcept C17409809 @default.
• W2095284584 hasConcept C189950617 @default.
• W2095284584 hasConcept C192562407 @default.
• W2095284584 hasConcept C2780049196 @default.
• W2095284584 hasConcept C87355193 @default.
• W2095284584 hasConceptScore W2095284584C111472728 @default.
• W2095284584 hasConceptScore W2095284584C121332964 @default.
• W2095284584 hasConceptScore W2095284584C127313418 @default.
• W2095284584 hasConceptScore W2095284584C138885662 @default.
• W2095284584 hasConceptScore W2095284584C17409809 @default.
• W2095284584 hasConceptScore W2095284584C189950617 @default.
• W2095284584 hasConceptScore W2095284584C192562407 @default.
• W2095284584 hasConceptScore W2095284584C2780049196 @default.
• W2095284584 hasConceptScore W2095284584C87355193 @default.
• W2095284584 hasIssue "3" @default.
• W2095284584 hasLocation W20952845841 @default.
• W2095284584 hasLocation W20952845842 @default.
• W2095284584 hasOpenAccess W2095284584 @default.
• W2095284584 hasPrimaryLocation W20952845841 @default.
• W2095284584 hasRelatedWork W1968103666 @default.
• W2095284584 hasRelatedWork W1990704426 @default.
• W2095284584 hasRelatedWork W2069865064 @default.
• W2095284584 hasRelatedWork W2107685972 @default.
• W2095284584 hasRelatedWork W2338692387 @default.
• W2095284584 hasRelatedWork W2378917733 @default.
• W2095284584 hasRelatedWork W2382977514 @default.
• W2095284584 hasRelatedWork W2991105498 @default.
• W2095284584 hasRelatedWork W4224008482 @default.
• W2095284584 hasRelatedWork W4307814549 @default.
• W2095284584 hasVolume "289" @default.
• W2095284584 isParatext "false" @default.
• W2095284584 isRetracted "false" @default.
• W2095284584 magId "2095284584" @default.
• W2095284584 workType "article" @default.