CoChat
Sign Up
Cited by 33Cancer-related Molecular PathwaysCell death mechanisms and regulationDrug Transport and Resistance Mechanisms

Rlip depletion prevents spontaneous neoplasia in TP53 null mice

Open access
Awasthi, Sanjay, Tompkins, Joshua, Singhal, Jyotsana, Riggs, Arthur D., Yadav, Sushma, Wu, Xiwei, Singh, Sharda, Warden, Charles +9 more·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1719586115PMC PMC5899455
Open this paper in CoChat — free account

Abstract

Significance: Mice that have homozygous deletion of the p53 tumor suppressor protein universally die of malignancy, generally before 6 months of age. We show that hemizygous deficiency of RALBP1 (RLIP76 or Rlip) confers a degree of protection from spontaneous malignancy that has never previously been observed. This discovery introduces a paradigm for p53 function, in which Rlip plays a central role as an effector that appears necessary for the cancer susceptibility of p53 null mice. Because p53 loss has a powerful effect on genomic instability that contributes to the initiation and promotion of cancers and to drug and radiation resistance in humans, our findings provide a method for prevention and therapy of p53-deficient cancer.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1719586115

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Rlip depletion by phosphorothioated DNA antisense results in broad methylomic and transcriptomic changes in livers of p53 KO mice relative to controls.

    “This is supported by recent findings that Rlip depletion by phosphorothioated DNA antisense results in broad methylomic and transcriptomic changes in the livers of p53 KO mice, relative to controls treated with scrambled phosphorothioate [39].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [39]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 69

  1. [1]Lane DP 1992 Cancer. p53, guardian of the genome Nature 358 15 16 1614522
  2. [3]Zilfou JT Lowe SW 2009 Tumor suppressive functions of p53 Cold Spring Harb Perspect Biol 1 a001883 20066118 PMC2773645
  3. [4]Donehower LA Lozano G 2009 20 years studying p53 functions in genetically engineered mice Nat Rev Cancer 9 831 841 19776746
  4. [5]Ariffin H 2014 Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome Proc Natl Acad Sci USA 111 15497 15501 25313051 PMC4217424
  5. [6]Villani A 2011 Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study Lancet Oncol 12 559 567 21601526
  6. [7]Nantasanti S Toussaint MJ Youssef SA Tooten PC de Bruin A 2016 Rb and p53 liver functions are essential for xenobiotic metabolism and tumor suppression PLoS One 11 e0150064 26967735 PMC4788452
  7. [8]Sablina AA 2005 The antioxidant function of the p53 tumor suppressor Nat Med 11 1306 1313 16286925 PMC2637821
  8. [9]Shetzer Y 2014 The paradigm of mutant p53-expressing cancer stem cells and drug resistance Carcinogenesis 35 1196 1208 24658181
  9. [10]Awasthi S 2000 Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin Biochemistry 39 9327 9334 10924126
  10. [11]Awasthi S 2001 Functional reassembly of ATP-dependent xenobiotic transport by the N- and C-terminal domains of RLIP76 and identification of ATP binding sequences Biochemistry 40 4159 4168 11300797
  11. [12]Awasthi S 1998 ATP-dependent human erythrocyte glutathione-conjugate transporter. II. Functional reconstitution of transport activity Biochemistry 37 5239 5248 9548755
  12. [13]Awasthi S 1998 ATP-dependent human erythrocyte glutathione-conjugate transporter. I. Purification, photoaffinity labeling, and kinetic characteristics of ATPase activity Biochemistry 37 5231 5238 9548754
  13. [14]Awasthi S 1994 Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein J Clin Invest 93 958 965 7907606 PMC294005
  14. [15]Awasthi S 2005 RLIP76 is a major determinant of radiation sensitivity Cancer Res 65 6022 6028 16024601
  15. [16]Awasthi S 2010 A central role of RLIP76 in regulation of glycemic control Diabetes 59 714 725 20007934 PMC2828645
  16. [17]Cheng JZ 2001 Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress J Biol Chem 276 41213 41223 11522795
  17. [18]Leake K Singhal J Nagaprashantha LD Awasthi S Singhal SS 2012 RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer PLoS One 7 e34582 22509328 PMC3317991
  18. [19]Sharma R Singhal SS Wickramarachchi D Awasthi YC Awasthi S 2004 RLIP76 (RALBP1)-mediated transport of leukotriene C4 (LTC4) in cancer cells: Implications in drug resistance Int J Cancer 112 934 942 15386349
  19. [20]Awasthi S 2008 RLIP76 and cancer Clin Cancer Res 14 4372 4377 18628450 PMC2919285
  20. [21]Nagaprashantha L Vartak N Awasthi S Awasthi S Singhal SS 2012 Novel anti-cancer compounds for developing combinatorial therapies to target anoikis-resistant tumors Pharm Res 29 621 636 22203324
  21. [22]Drake KJ 2007 RALBP1/RLIP76 mediates multidrug resistance Int J Oncol 30 139 144 17143522
  22. [23]Figarola JL 2013 COH-SR4 reduces body weight, improves glycemic control and prevents hepatic steatosis in high fat diet-induced obese mice PLoS One 8 e83801 24376752 PMC3869817
  23. [24]Singhal SS 2007 Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (Ral-binding protein 1) Cancer Res 67 4382 4389 17483352
  24. [25]Singhal SS 2009 RLIP76: A target for kidney cancer therapy Cancer Res 69 4244 4251 19417134 PMC2921230
  25. [26]Singhal SS 2011 Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis Mol Cancer Ther 10 16 28 21220488 PMC3065778
  26. [27]Singhal SS Yadav S Drake K Singhal J Awasthi S 2008 Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1 J Biol Chem 283 19714 19729 18474607 PMC2443664
  27. [28]Stuckler D 2005 RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer Cancer Res 65 991 998 15705900
  28. [29]Yadav S 2004 Identification of membrane-anchoring domains of RLIP76 using deletion mutant analyses Biochemistry 43 16243 16253 15610018
  29. [30]Yang Y 2003 Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: Role of 4-hydroxynonenal in UVA-mediated signaling for apoptosis J Biol Chem 278 41380 41388 12888579
  30. [31]Burg D Mulder GJ 2002 Glutathione conjugates and their synthetic derivatives as inhibitors of glutathione-dependent enzymes involved in cancer and drug resistance Drug Metab Rev 34 821 863 12487151
  31. [32]Brown MS Goldstein JL 1979 Receptor-mediated endocytosis: Insights from the lipoprotein receptor system Proc Natl Acad Sci USA 76 3330 3337 226968 PMC383819
  32. [33]Sorkin A von Zastrow M 2009 Endocytosis and signalling: Intertwining molecular networks Nat Rev Mol Cell Biol 10 609 622 19696798 PMC2895425
  33. [34]Jean S 2010 Extended-synaptotagmin-2 mediates FGF receptor endocytosis and ERK activation in vivo Dev Cell 19 426 439 20833364
  34. [35]Pinilla-Macua I Sorkin A 2015 Methods to study endocytic trafficking of the EGF receptor Methods Cell Biol 130 347 367 26360045 PMC4836846
  35. [36]Singhal SS 2010 Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer Int J Cancer 126 1327 1338 19626587 PMC3065777
  36. [37]Tsujimoto M Yip YK Vilcek J 1985 Tumor necrosis factor: Specific binding and internalization in sensitive and resistant cells Proc Natl Acad Sci USA 82 7626 7630 2999773 PMC391386
  37. [38]Fillatre J 2012 Dynamics of the subcellular localization of RalBP1/RLIP through the cell cycle: The role of targeting signals and of protein-protein interactions FASEB J 26 2164 2174 22319010
  38. [39]Hinoi T 1996 Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator J Biol Chem 271 19710 19716 8702675
  39. [40]Jullien-Flores V 2000 RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: Involvement of the Ral pathway in receptor endocytosis J Cell Sci 113 2837 2844 10910768
  40. [41]Kashatus DF 2011 RALA and RALBP1 regulate mitochondrial fission at mitosis Nat Cell Biol 13 1108 1115 21822277 PMC3167028
  41. [42]Lee S Goldfinger LE 2014 RLIP76 regulates HIF-1 activity, VEGF expression and secretion in tumor cells, and secretome transactivation of endothelial cells FASEB J 28 4158 4168 24928198 PMC4139904
  42. [43]Lee S Wurtzel JG Singhal SS Awasthi S Goldfinger LE 2012 RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization Cancer Res 72 5165 5173 22902412 PMC3473090
  43. [44]Rossé C L’Hoste S Offner N Picard A Camonis J 2003 RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate epsin during the switch off of endocytosis in mitosis J Biol Chem 278 30597 30604 12775724
  44. [45]Wurtzel JG 2015 RLIP76 regulates Arf6-dependent cell spreading and migration by linking ARNO with activated R-Ras at recycling endosomes Biochem Biophys Res Commun 467 785 791 26498519 PMC4644438
  45. [46]Prasanna PG 2015 Radioprotectors and radiomitigators for improving radiation therapy: The small business innovation research (SBIR) gateway for accelerating clinical translation Radiat Res 184 235 248 26284423 PMC4581592
  46. [47]Singhal J Nagaprashantha L Vatsyayan R Awasthi S Singhal SS 2011 RLIP76, a glutathione-conjugate transporter, plays a major role in the pathogenesis of metabolic syndrome PLoS One 6 e24688 21931813 PMC3172288
  47. [48]Morris SM 2008 Effect of p53 genotype on gene expression profiles in murine liver Mutat Res 640 54 73 18206960
  48. [49]Uren AG 2008 Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks Cell 133 727 741 18485879 PMC2405818
  49. [50]Goding CR Pei D Lu X 2014 Cancer: Pathological nuclear reprogramming? Nat Rev Cancer 14 568 573 25030952
  50. [51]Suzuki H Yamamoto E Maruyama R Niinuma T Kai M 2014 Biological significance of the CpG island methylator phenotype Biochem Biophys Res Commun 455 35 42 25016183
  51. [52]Kulis M Esteller M 2010 DNA methylation and cancer Adv Genet 70 27 56 20920744
  52. [53]Singhal J 2017 2′-Hydroxyflavanone: A novel strategy for targeting breast cancer Oncotarget 8 75025 75037 29088842 PMC5650397
  53. [54]Ames BN Shigenaga MK Gold LS 1993 DNA lesions, inducible DNA repair, and cell division: Three key factors in mutagenesis and carcinogenesis Environ Health Perspect 101 35 44 PMC1519422 8013423
  54. [55]Deferme L 2016 Dynamic interplay between the transcriptome and methylome in response to oxidative and alkylating stress Chem Res Toxicol 29 1428 1438 27509014
  55. [56]Esterbauer H Schaur RJ Zollner H 1991 Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes Free Radic Biol Med 11 81 128 1937131
  56. [57]Shigenaga MK Gimeno CJ Ames BN 1989 Urinary 8-hydroxy-2′-deoxyguanosine as a biological marker of in vivo oxidative DNA damage Proc Natl Acad Sci USA 86 9697 9701 2602371 PMC298568
  57. [58]Li Q Martinez JD 2011 P53 is transported into the nucleus via an Hsf1-dependent nuclear localization mechanism Mol Carcinog 50 143 152 21229611 PMC3735450
  58. [59]Hu Y Mivechi NF 2003 HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo J Biol Chem 278 17299 17306 12621024
  59. [60]Min JN Huang L Zimonjic DB Moskophidis D Mivechi NF 2007 Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors Oncogene 26 5086 5097 17310987
  60. [61]Morinaka K 1999 Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis Oncogene 18 5915 5922 10557078
  61. [62]Nakashima S 1999 Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors EMBO J 18 3629 3642 10393179 PMC1171441
  62. [63]Yamaguchi A Urano T Goi T Feig LA 1997 An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1 J Biol Chem 272 31230 31234 9395447
  63. [64]Enari M Ohmori K Kitabayashi I Taya Y 2006 Requirement of clathrin heavy chain for p53-mediated transcription Genes Dev 20 1087 1099 16618797 PMC1472469
  64. [65]Endo Y 2008 Regulation of clathrin-mediated endocytosis by p53 Genes Cells 13 375 386 18363968
  65. [66]Li H Ruan J Durbin R 2008 Mapping short DNA sequencing reads and calling variants using mapping quality scores Genome Res 18 1851 1858 18714091 PMC2577856
  66. [67]Li R Li Y Kristiansen K Wang J 2008 SOAP: Short oligonucleotide alignment program Bioinformatics 24 713 714 18227114
  67. [68]Hahn MA Li AX Wu X Pfeifer GP 2015 Cancer Epigenetics Methods Mol Biol 1238 273 287 25421665 PMC4340590
  68. [69]Krueger F Andrews SR 2011 Bismark: A flexible aligner and methylation caller for bisulfite-seq applications Bioinformatics 27 1571 1572 21493656 PMC3102221
  69. [70]Li LC Dahiya R 2002 MethPrimer: Designing primers for methylation PCRs Bioinformatics 18 1427 1431 12424112

Cited by

Sorted by citations

Authors
Awasthi, S., Tompkins, J., Singhal, J., Riggs, A. D., Yadav, S., Wu, X., Singh, S., Warden, C., Liu, Z., Wang, J., Slavin, T. P., Weitzel, J. N., Yuan, Y.-C., Awasthi, M., Srivastava, S. K., Awasthi, Y. C., & Singhal, S. S.
Affiliations
  • Division of Hematology & Oncology, Department of Internal Medicine, Texas Tech Health Sciences Center, Lubbock, TX 79430-9410;
  • City Of Hope National Medical Center (US)
  • Texas Tech University (US)
  • Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555-0647
Corresponding author
Riggs, Arthur D.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-03-23
Volume
115
Issue
15
Pages
3918-3923
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1719586115
PMC
PMC5899455
OpenAlex
W2790875256
Cited by
33
References
1
Citations by year
2026: 2 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 1
FWCI
1.78
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • NIH/NCI (CA77495, CA129383)
  • DOD (W81XWH-16-1-0641)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
RALBP1, RLIP76, p53, spontaneous tumors, cancer susceptibility, tumor suppressor function, genomic instability, drug resistance, radioresistance (biology), cancer prevention
MeSH terms
Animals, Female, Humans, Male, Mice, Inbred C57BL, Neoplasms, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, GTPase-Activating Proteins, Tumor Suppressor Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review