p53 mutation regulates PKD genes and results in co-occurrence of PKD and tumorigenesis
|
摘要
Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc~(-/-)WRN~(-/-)p53~(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc~(-/-)WRN~(-/-)p53~(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
Objective: Polycystic kidney disease(PKD) is the major cause of kidney failure and mortality in humans. It has always been suspected that the development of cystic kidney disease shares features with tumorigenesis, although the evidence is unclear.Methods: We crossed p53 mutant mice(p53N236S, p53S) with Werner syndrome mice and analyzed the pathological phenotypes.The RNA-seq, ss GSEA analysis, and real-time PCR were performed to dissect the gene signatures involved in the development of disease phenotypes.Results: We found enlarged kidneys with fluid-filled cysts in offspring mice with a genotype of G3mTerc~(-/-)WRN~(-/-)p53~(S/S)(G3TM).Pathology analysis confirmed the occurrence of PKD, and it was highly correlated with the incidence of tumorigenesis. RNA-seq data revealed the gene signatures involved in PKD development, and demonstrated that PKD and tumorigenesis shared common pathways, including complement pathways, lipid metabolism, mitochondria energy homeostasis and others. Interestingly, this G3TM PKD and the classical PKD1/2 deficient PKD shared common pathways, possibly because the mutant p53S could regulate the expression levels of PKD1/2, Pkhd1, and Hnf1b.Conclusions: We established a dual mouse model for PKD and tumorigenesis derived from abnormal cellular proliferation and telomere dysfunction. The innovative point of our study is to report PKD occurring in conjunction with tumorigenesis. The gene signatures revealed might shed new light on the pathogenesis of PKD, and provide new molecular biomarkers for clinical diagnosis and prognosis.
引文
1.Harris PC,Torres VE.Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease.J Clin Invest.2014;124:2315-24.
2.Mangolini A,de Stephanis L,Aguiari G.Role of calcium in polycystic kidney disease:From signaling to pathology.World JNephrol.2016;5:76-83.
3.Nishio S,Hatano M,Nagata M,Horie S,Koike T,Tokuhisa T,et al.Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.J Clin Invest.2005;115:910-8.
4.Van Bodegom D,Saifudeen Z,Dipp S,Puri S,Magenheimer BS,Calvet JP,et al.The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression.J Biol Chem.2006;281:31234-44.
5.Islam MR,Jimenez T,Pelham C,Rodova M,Puri S,Magenheimer BS,et al.MAP/ERK kinase kinase 1(MEKK1)mediates transcriptional repression by interacting with polycystic kidney disease-1(PKD1)promoter-bound p53 tumor suppressor protein.JBiol Chem.2010;285:38818-31.
6.Varela A,Piperi C,Sigala F,Agrogiannis G,Davos CH,Andri MA,et al.Elevated expression of mechanosensory polycystins in human carotid atherosclerotic plaques:Association with p53 activation and disease severity.Sci Rep.2015;5:13461.
7.Li X,Miao X,Wang HS,Xu ZX,Li B.The tissue dependent interactions between p53 and Bcl-2 in vivo.Oncotarget.2015;6:35699-709.
8.Veis DJ,Sorenson CM,Shutter JR,Korsmeyer SJ.Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair.Cell.1993;75:229-40.
9.Kim MP,Lozano G.Mutant p53 partners in crime.Cell Death Differ.2018;25:161-8.
10.Chu WK,Hickson ID.Recq helicases:Multifunctional genome caretakers.Nat Rev Cancer.2009;9:644-54.
11.Ozgenc A,Loeb LA.Werner syndrome,aging and cancer.Genome Dyn.2006;1:206-17.
12.Crabbe L,Verdun RE,Haggblom CI,Karlseder J.Defective telomere lagging strand synthesis in cells lacking wrn helicase activity.Science.2004;306:1951-3.
13.Palm W,de Lange T.How shelterin protects mammalian telomeres.Annu Rev Genet.2008;42:301-34.
14.Lebel M,Leder P.A deletion within the murine werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity.Proc Natl Acad Sci USA.1998;95:13097-102.
15.Chang S,Multani AS,Cabrera NG,Naylor ML,Laud P,Lombard D,et al.Essential role of limiting telomeres in the pathogenesis of werner syndrome.Nat Genet.2004;36:877-82.
16.Du XB,Shen J,Kugan N,Furth EE,Lombard DB,Cheung C,et al.Telomere shortening exposes functions for the mouse werner and bloom syndrome genes.Mol Cell Biol.2004;24:8437-46.
17.Zhao LJ,Wang BY,Zhao XL,Wu XM,Zhang QS,Wei CY,et al.Gain of function in the mouse model of a recurrent mutation p53N236S promotes the formation of double minute chromosomes and the oncogenic potential of p19ARF.Mol Carcinog.2018;57:147-58.
18.Chen X,Chang JT.Planning bioinformatics workflows using an expert system.Bioinformatics.2017;33:1210-5.
19.Subramanian A,Tamayo P,Mootha VK,Mukherjee S,Ebert BL,Gillette MA,et al.Gene set enrichment analysis:A knowledgebased approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci USA.2005;102:15545-50.
20.Liberzon A,Subramanian A,Pinchback R,Thorvaldsdottir H,Tamayo P,Mesirov JP.Molecular signatures database(MSig DB)3.0.Bioinformatics.2011;27:1739-40.
21.Ong ACM,Harris PC.A polycystin-centric view of cyst formation and disease:The polycystins revisited.Kidney Int.2015;88:699-710.
22.Woo YM,Kim DY,Koo NJ,Kim YM,Lee S,Ko JY,et al.Profiling of mi RNAs and target genes related to cystogenesis in ADPKDmouse models.Sci Rep.2017;7:14151.
23.Gresh L,Fischer E,Reimann A,Tanguy M,Garbay S,Shao XL,et al.A transcriptional network in polycystic kidney disease.EMBO J.2004;23:1657-68.
24.Kovács J,Gomba S,Zilahy M.Comparison of the morphology of renal cysts and cystic renal tumors.Pathol Oncol Res.1997;3:272-7.
25.Lanoix J,D'Agati V,Szabolcs M,Trudel M.Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease(ADPKD).Oncogene.1996;13:1153-60.
26.Kastenhuber ER,Lowe SW.Putting p53 in context.Cell.2017;170:1062-78.
27.Kim H,Bae Y,Jeong W,Ahn C,Kang S.Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition.Eur J Hum Genet.2004;12:433-40.
28.De Vriese AS,Sethi S,Van Praet J,Nath KA,Fervenza FC.Kidney disease caused by dysregulation of the complement alternative pathway:An etiologic approach.J Am Soc Nephrol.2015;26:2917-29.
29.Su Z,Wang X,Gao X,Liu Y,Pan C,Hu H,et al.Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease.J Intern Med.2014;276:470-85.
30.Emma F,Montini G,Parikh SM,Salviati L.Mitochondrial dysfunction in inherited renal disease and acute kidney injury.Nat Rev.2016;12:267-80.
31.Bhargava P,Schnellmann RG.Mitochondrial energetics in the kidney.Nat Rev.2017;13:629-46.
32.Faguer S,Chassaing N,Bandin F,Prouheze C,Garnier A,Casemayou A,et al.The HNF1B score is a simple tool to select patients for HNF1B gene analysis.Kidney Int.2014;86:1007-15.
2.Mangolini A,de Stephanis L,Aguiari G.Role of calcium in polycystic kidney disease:From signaling to pathology.World JNephrol.2016;5:76-83.
3.Nishio S,Hatano M,Nagata M,Horie S,Koike T,Tokuhisa T,et al.Pkd1 regulates immortalized proliferation of renal tubular epithelial cells through p53 induction and JNK activation.J Clin Invest.2005;115:910-8.
4.Van Bodegom D,Saifudeen Z,Dipp S,Puri S,Magenheimer BS,Calvet JP,et al.The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression.J Biol Chem.2006;281:31234-44.
5.Islam MR,Jimenez T,Pelham C,Rodova M,Puri S,Magenheimer BS,et al.MAP/ERK kinase kinase 1(MEKK1)mediates transcriptional repression by interacting with polycystic kidney disease-1(PKD1)promoter-bound p53 tumor suppressor protein.JBiol Chem.2010;285:38818-31.
6.Varela A,Piperi C,Sigala F,Agrogiannis G,Davos CH,Andri MA,et al.Elevated expression of mechanosensory polycystins in human carotid atherosclerotic plaques:Association with p53 activation and disease severity.Sci Rep.2015;5:13461.
7.Li X,Miao X,Wang HS,Xu ZX,Li B.The tissue dependent interactions between p53 and Bcl-2 in vivo.Oncotarget.2015;6:35699-709.
8.Veis DJ,Sorenson CM,Shutter JR,Korsmeyer SJ.Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair.Cell.1993;75:229-40.
9.Kim MP,Lozano G.Mutant p53 partners in crime.Cell Death Differ.2018;25:161-8.
10.Chu WK,Hickson ID.Recq helicases:Multifunctional genome caretakers.Nat Rev Cancer.2009;9:644-54.
11.Ozgenc A,Loeb LA.Werner syndrome,aging and cancer.Genome Dyn.2006;1:206-17.
12.Crabbe L,Verdun RE,Haggblom CI,Karlseder J.Defective telomere lagging strand synthesis in cells lacking wrn helicase activity.Science.2004;306:1951-3.
13.Palm W,de Lange T.How shelterin protects mammalian telomeres.Annu Rev Genet.2008;42:301-34.
14.Lebel M,Leder P.A deletion within the murine werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity.Proc Natl Acad Sci USA.1998;95:13097-102.
15.Chang S,Multani AS,Cabrera NG,Naylor ML,Laud P,Lombard D,et al.Essential role of limiting telomeres in the pathogenesis of werner syndrome.Nat Genet.2004;36:877-82.
16.Du XB,Shen J,Kugan N,Furth EE,Lombard DB,Cheung C,et al.Telomere shortening exposes functions for the mouse werner and bloom syndrome genes.Mol Cell Biol.2004;24:8437-46.
17.Zhao LJ,Wang BY,Zhao XL,Wu XM,Zhang QS,Wei CY,et al.Gain of function in the mouse model of a recurrent mutation p53N236S promotes the formation of double minute chromosomes and the oncogenic potential of p19ARF.Mol Carcinog.2018;57:147-58.
18.Chen X,Chang JT.Planning bioinformatics workflows using an expert system.Bioinformatics.2017;33:1210-5.
19.Subramanian A,Tamayo P,Mootha VK,Mukherjee S,Ebert BL,Gillette MA,et al.Gene set enrichment analysis:A knowledgebased approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci USA.2005;102:15545-50.
20.Liberzon A,Subramanian A,Pinchback R,Thorvaldsdottir H,Tamayo P,Mesirov JP.Molecular signatures database(MSig DB)3.0.Bioinformatics.2011;27:1739-40.
21.Ong ACM,Harris PC.A polycystin-centric view of cyst formation and disease:The polycystins revisited.Kidney Int.2015;88:699-710.
22.Woo YM,Kim DY,Koo NJ,Kim YM,Lee S,Ko JY,et al.Profiling of mi RNAs and target genes related to cystogenesis in ADPKDmouse models.Sci Rep.2017;7:14151.
23.Gresh L,Fischer E,Reimann A,Tanguy M,Garbay S,Shao XL,et al.A transcriptional network in polycystic kidney disease.EMBO J.2004;23:1657-68.
24.Kovács J,Gomba S,Zilahy M.Comparison of the morphology of renal cysts and cystic renal tumors.Pathol Oncol Res.1997;3:272-7.
25.Lanoix J,D'Agati V,Szabolcs M,Trudel M.Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease(ADPKD).Oncogene.1996;13:1153-60.
26.Kastenhuber ER,Lowe SW.Putting p53 in context.Cell.2017;170:1062-78.
27.Kim H,Bae Y,Jeong W,Ahn C,Kang S.Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition.Eur J Hum Genet.2004;12:433-40.
28.De Vriese AS,Sethi S,Van Praet J,Nath KA,Fervenza FC.Kidney disease caused by dysregulation of the complement alternative pathway:An etiologic approach.J Am Soc Nephrol.2015;26:2917-29.
29.Su Z,Wang X,Gao X,Liu Y,Pan C,Hu H,et al.Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease.J Intern Med.2014;276:470-85.
30.Emma F,Montini G,Parikh SM,Salviati L.Mitochondrial dysfunction in inherited renal disease and acute kidney injury.Nat Rev.2016;12:267-80.
31.Bhargava P,Schnellmann RG.Mitochondrial energetics in the kidney.Nat Rev.2017;13:629-46.
32.Faguer S,Chassaing N,Bandin F,Prouheze C,Garnier A,Casemayou A,et al.The HNF1B score is a simple tool to select patients for HNF1B gene analysis.Kidney Int.2014;86:1007-15.