Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Jan 15;17(2):554–564. doi: 10.1093/emboj/17.2.554

Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein.

J Roth 1, M Dobbelstein 1, D A Freedman 1, T Shenk 1, A J Levine 1
PMCID: PMC1170405  PMID: 9430646

Abstract

The hdm2 gene is overexpressed in a variety of human tumors. Its gene product localizes predominantly to the nucleus, where it acts as an inhibitor of the p53 tumor suppressor gene product. It is shown here that the hdm2 oncoprotein constantly shuttles between the nucleus and the cytoplasm. Shuttling of hdm2 does not depend on its interaction with p53. Nuclear export of hdm2 is mediated by a signal sequence similar to the nuclear export signal of the rev protein from human immunodeficiency virus and other lentiviruses. Mutation of this signal sequence abolishes detectable nucleo-cytoplasmic shuttling. When fused to a carrier protein, the hdm2 signal sequence can mediate nuclear export after intranuclear microinjection into HeLa cells. The export of hdm2 can be blocked by a competitive inhibitor of rev export, arguing that the export pathways for hdm2 and rev are either overlapping or identical. Inhibition of its export modifies the ability of hdm2 to block p53-mediated transcriptional activation, and hdm2's export function is required to accelerate the degradation of p53. Thus the rev nuclear export pathway may be used to regulate an oncogene product's activity and modulate cellular growth.

Full Text

The Full Text of this article is available as a PDF (450.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Babiss L. E., Ginsberg H. S., Darnell J. E., Jr Adenovirus E1B proteins are required for accumulation of late viral mRNA and for effects on cellular mRNA translation and transport. Mol Cell Biol. 1985 Oct;5(10):2552–2558. doi: 10.1128/mcb.5.10.2552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barak Y., Gottlieb E., Juven-Gershon T., Oren M. Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev. 1994 Aug 1;8(15):1739–1749. doi: 10.1101/gad.8.15.1739. [DOI] [PubMed] [Google Scholar]
  3. Berberich S., Cole M. The mdm-2 oncogene is translocated and overexpressed in a murine plasmacytoma cell line expressing wild-type p53. Oncogene. 1994 May;9(5):1469–1472. [PubMed] [Google Scholar]
  4. Bevec D., Jaksche H., Oft M., Wöhl T., Himmelspach M., Pacher A., Schebesta M., Koettnitz K., Dobrovnik M., Csonga R. Inhibition of HIV-1 replication in lymphocytes by mutants of the Rev cofactor eIF-5A. Science. 1996 Mar 29;271(5257):1858–1860. doi: 10.1126/science.271.5257.1858. [DOI] [PubMed] [Google Scholar]
  5. Bogerd H. P., Fridell R. A., Benson R. E., Hua J., Cullen B. R. Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay. Mol Cell Biol. 1996 Aug;16(8):4207–4214. doi: 10.1128/mcb.16.8.4207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bogerd H. P., Fridell R. A., Madore S., Cullen B. R. Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins. Cell. 1995 Aug 11;82(3):485–494. doi: 10.1016/0092-8674(95)90437-9. [DOI] [PubMed] [Google Scholar]
  7. Boulikas T. Nuclear localization signals (NLS). Crit Rev Eukaryot Gene Expr. 1993;3(3):193–227. [PubMed] [Google Scholar]
  8. Bueso-Ramos C. E., Yang Y., deLeon E., McCown P., Stass S. A., Albitar M. The human MDM-2 oncogene is overexpressed in leukemias. Blood. 1993 Nov 1;82(9):2617–2623. [PubMed] [Google Scholar]
  9. Chen J., Lin J., Levine A. J. Regulation of transcription functions of the p53 tumor suppressor by the mdm-2 oncogene. Mol Med. 1995 Jan;1(2):142–152. [PMC free article] [PubMed] [Google Scholar]
  10. Chen J., Marechal V., Levine A. J. Mapping of the p53 and mdm-2 interaction domains. Mol Cell Biol. 1993 Jul;13(7):4107–4114. doi: 10.1128/mcb.13.7.4107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen J., Wu X., Lin J., Levine A. J. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol Cell Biol. 1996 May;16(5):2445–2452. doi: 10.1128/mcb.16.5.2445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cordon-Cardo C., Latres E., Drobnjak M., Oliva M. R., Pollack D., Woodruff J. M., Marechal V., Chen J., Brennan M. F., Levine A. J. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 1994 Feb 1;54(3):794–799. [PubMed] [Google Scholar]
  13. Dietrich C., Bartsch T., Schanz F., Oesch F., Wieser R. J. p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10815–10819. doi: 10.1073/pnas.93.20.10815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dobbelstein M., Arthur A. K., Dehde S., van Zee K., Dickmanns A., Fanning E. Intracistronic complementation reveals a new function of SV40 T antigen that co-operates with Rb and p53 binding to stimulate DNA synthesis in quiescent cells. Oncogene. 1992 May;7(5):837–847. [PubMed] [Google Scholar]
  15. Dobbelstein M., Roth J., Kimberly W. T., Levine A. J., Shenk T. Nuclear export of the E1B 55-kDa and E4 34-kDa adenoviral oncoproteins mediated by a rev-like signal sequence. EMBO J. 1997 Jul 16;16(14):4276–4284. doi: 10.1093/emboj/16.14.4276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dobbelstein M., Shenk T. In vitro selection of RNA ligands for the ribosomal L22 protein associated with Epstein-Barr virus-expressed RNA by using randomized and cDNA-derived RNA libraries. J Virol. 1995 Dec;69(12):8027–8034. doi: 10.1128/jvi.69.12.8027-8034.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dobbelstein M., Shenk T. Protection against apoptosis by the vaccinia virus SPI-2 (B13R) gene product. J Virol. 1996 Sep;70(9):6479–6485. doi: 10.1128/jvi.70.9.6479-6485.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dobner T., Horikoshi N., Rubenwolf S., Shenk T. Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science. 1996 Jun 7;272(5267):1470–1473. doi: 10.1126/science.272.5267.1470. [DOI] [PubMed] [Google Scholar]
  19. Elenbaas B., Dobbelstein M., Roth J., Shenk T., Levine A. J. The MDM2 oncoprotein binds specifically to RNA through its RING finger domain. Mol Med. 1996 Jul;2(4):439–451. [PMC free article] [PubMed] [Google Scholar]
  20. Fiddler T. A., Smith L., Tapscott S. J., Thayer M. J. Amplification of MDM2 inhibits MyoD-mediated myogenesis. Mol Cell Biol. 1996 Sep;16(9):5048–5057. doi: 10.1128/mcb.16.9.5048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Finlay C. A. The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth. Mol Cell Biol. 1993 Jan;13(1):301–306. doi: 10.1128/mcb.13.1.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fischer U., Huber J., Boelens W. C., Mattaj I. W., Lührmann R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell. 1995 Aug 11;82(3):475–483. doi: 10.1016/0092-8674(95)90436-0. [DOI] [PubMed] [Google Scholar]
  23. Freedman D. A., Epstein C. B., Roth J. C., Levine A. J. A genetic approach to mapping the p53 binding site in the MDM2 protein. Mol Med. 1997 Apr;3(4):248–259. [PMC free article] [PubMed] [Google Scholar]
  24. Fridell R. A., Fischer U., Lührmann R., Meyer B. E., Meinkoth J. L., Malim M. H., Cullen B. R. Amphibian transcription factor IIIA proteins contain a sequence element functionally equivalent to the nuclear export signal of human immunodeficiency virus type 1 Rev. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2936–2940. doi: 10.1073/pnas.93.7.2936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fritz C. C., Zapp M. L., Green M. R. A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature. 1995 Aug 10;376(6540):530–533. doi: 10.1038/376530a0. [DOI] [PubMed] [Google Scholar]
  26. Gannon J. V., Lane D. P. Protein synthesis required to anchor a mutant p53 protein which is temperature-sensitive for nuclear transport. Nature. 1991 Feb 28;349(6312):802–806. doi: 10.1038/349802a0. [DOI] [PubMed] [Google Scholar]
  27. Gerace L. Nuclear export signals and the fast track to the cytoplasm. Cell. 1995 Aug 11;82(3):341–344. doi: 10.1016/0092-8674(95)90420-4. [DOI] [PubMed] [Google Scholar]
  28. Goodrum F. D., Shenk T., Ornelles D. A. Adenovirus early region 4 34-kilodalton protein directs the nuclear localization of the early region 1B 55-kilodalton protein in primate cells. J Virol. 1996 Sep;70(9):6323–6335. doi: 10.1128/jvi.70.9.6323-6335.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Gottlieb T. M., Jackson S. P. The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell. 1993 Jan 15;72(1):131–142. doi: 10.1016/0092-8674(93)90057-w. [DOI] [PubMed] [Google Scholar]
  30. Guddat U., Bakken A. H., Pieler T. Protein-mediated nuclear export of RNA: 5S rRNA containing small RNPs in xenopus oocytes. Cell. 1990 Feb 23;60(4):619–628. doi: 10.1016/0092-8674(90)90665-2. [DOI] [PubMed] [Google Scholar]
  31. Görlich D., Mattaj I. W. Nucleocytoplasmic transport. Science. 1996 Mar 15;271(5255):1513–1518. doi: 10.1126/science.271.5255.1513. [DOI] [PubMed] [Google Scholar]
  32. Haines D. S., Landers J. E., Engle L. J., George D. L. Physical and functional interaction between wild-type p53 and mdm2 proteins. Mol Cell Biol. 1994 Feb;14(2):1171–1178. doi: 10.1128/mcb.14.2.1171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Halbert D. N., Cutt J. R., Shenk T. Adenovirus early region 4 encodes functions required for efficient DNA replication, late gene expression, and host cell shutoff. J Virol. 1985 Oct;56(1):250–257. doi: 10.1128/jvi.56.1.250-257.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997 May 15;387(6630):296–299. doi: 10.1038/387296a0. [DOI] [PubMed] [Google Scholar]
  35. Hope T. J., Bond B. L., McDonald D., Klein N. P., Parslow T. G. Effector domains of human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex are functionally interchangeable and share an essential peptide motif. J Virol. 1991 Nov;65(11):6001–6007. doi: 10.1128/jvi.65.11.6001-6007.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Izaurralde E., Mattaj I. W. RNA export. Cell. 1995 Apr 21;81(2):153–159. doi: 10.1016/0092-8674(95)90323-2. [DOI] [PubMed] [Google Scholar]
  37. Jarmolowski A., Boelens W. C., Izaurralde E., Mattaj I. W. Nuclear export of different classes of RNA is mediated by specific factors. J Cell Biol. 1994 Mar;124(5):627–635. doi: 10.1083/jcb.124.5.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Jentsch S., Schlenker S. Selective protein degradation: a journey's end within the proteasome. Cell. 1995 Sep 22;82(6):881–884. doi: 10.1016/0092-8674(95)90021-7. [DOI] [PubMed] [Google Scholar]
  39. Jones S. N., Roe A. E., Donehower L. A., Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995 Nov 9;378(6553):206–208. doi: 10.1038/378206a0. [DOI] [PubMed] [Google Scholar]
  40. Kao C. C., Yew P. R., Berk A. J. Domains required for in vitro association between the cellular p53 and the adenovirus 2 E1B 55K proteins. Virology. 1990 Dec;179(2):806–814. doi: 10.1016/0042-6822(90)90148-k. [DOI] [PubMed] [Google Scholar]
  41. Katahira J., Ishizaki T., Sakai H., Adachi A., Yamamoto K., Shida H. Effects of translation initiation factor eIF-5A on the functioning of human T-cell leukemia virus type I Rex and human immunodeficiency virus Rev inhibited trans dominantly by a Rex mutant deficient in RNA binding. J Virol. 1995 May;69(5):3125–3133. doi: 10.1128/jvi.69.5.3125-3133.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Knippschild U., Oren M., Deppert W. Abrogation of wild-type p53 mediated growth-inhibition by nuclear exclusion. Oncogene. 1996 Apr 18;12(8):1755–1765. [PubMed] [Google Scholar]
  43. Kubbutat M. H., Jones S. N., Vousden K. H. Regulation of p53 stability by Mdm2. Nature. 1997 May 15;387(6630):299–303. doi: 10.1038/387299a0. [DOI] [PubMed] [Google Scholar]
  44. Kussie P. H., Gorina S., Marechal V., Elenbaas B., Moreau J., Levine A. J., Pavletich N. P. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science. 1996 Nov 8;274(5289):948–953. doi: 10.1126/science.274.5289.948. [DOI] [PubMed] [Google Scholar]
  45. Ladanyi M., Cha C., Lewis R., Jhanwar S. C., Huvos A. G., Healey J. H. MDM2 gene amplification in metastatic osteosarcoma. Cancer Res. 1993 Jan 1;53(1):16–18. [PubMed] [Google Scholar]
  46. Landers J. E., Haines D. S., Strauss J. F., 3rd, George D. L. Enhanced translation: a novel mechanism of mdm2 oncogene overexpression identified in human tumor cells. Oncogene. 1994 Sep;9(9):2745–2750. [PubMed] [Google Scholar]
  47. Leach F. S., Tokino T., Meltzer P., Burrell M., Oliner J. D., Smith S., Hill D. E., Sidransky D., Kinzler K. W., Vogelstein B. p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 1993 May 15;53(10 Suppl):2231–2234. [PubMed] [Google Scholar]
  48. Liang S., Hitomi M., Tartakoff A. M. Adenoviral E1B-55kDa protein inhibits yeast mRNA export and perturbs nuclear structure. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7372–7375. doi: 10.1073/pnas.92.16.7372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Lin J., Chen J., Elenbaas B., Levine A. J. Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev. 1994 May 15;8(10):1235–1246. doi: 10.1101/gad.8.10.1235. [DOI] [PubMed] [Google Scholar]
  50. Marechal V., Elenbaas B., Piette J., Nicolas J. C., Levine A. J. The ribosomal L5 protein is associated with mdm-2 and mdm-2-p53 complexes. Mol Cell Biol. 1994 Nov;14(11):7414–7420. doi: 10.1128/mcb.14.11.7414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Martin K., Trouche D., Hagemeier C., Sørensen T. S., La Thangue N. B., Kouzarides T. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature. 1995 Jun 22;375(6533):691–694. doi: 10.1038/375691a0. [DOI] [PubMed] [Google Scholar]
  52. McMasters K. M., Montes de Oca Luna R., Peña J. R., Lozano G. mdm2 deletion does not alter growth characteristics of p53-deficient embryo fibroblasts. Oncogene. 1996 Oct 17;13(8):1731–1736. [PubMed] [Google Scholar]
  53. Meyer B. E., Meinkoth J. L., Malim M. H. Nuclear transport of human immunodeficiency virus type 1, visna virus, and equine infectious anemia virus Rev proteins: identification of a family of transferable nuclear export signals. J Virol. 1996 Apr;70(4):2350–2359. doi: 10.1128/jvi.70.4.2350-2359.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Michael W. M., Choi M., Dreyfuss G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell. 1995 Nov 3;83(3):415–422. doi: 10.1016/0092-8674(95)90119-1. [DOI] [PubMed] [Google Scholar]
  55. Michael W. M., Dreyfuss G. Distinct domains in ribosomal protein L5 mediate 5 S rRNA binding and nucleolar localization. J Biol Chem. 1996 May 10;271(19):11571–11574. doi: 10.1074/jbc.271.19.11571. [DOI] [PubMed] [Google Scholar]
  56. Mittnacht S., Weinberg R. A. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment. Cell. 1991 May 3;65(3):381–393. doi: 10.1016/0092-8674(91)90456-9. [DOI] [PubMed] [Google Scholar]
  57. Moll U. M., LaQuaglia M., Bénard J., Riou G. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4407–4411. doi: 10.1073/pnas.92.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Moll U. M., Riou G., Levine A. J. Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7262–7266. doi: 10.1073/pnas.89.15.7262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Momand J., Zambetti G. P. Analysis of the proportion of p53 bound to mdm-2 in cells with defined growth characteristics. Oncogene. 1996 Jun 6;12(11):2279–2289. [PubMed] [Google Scholar]
  60. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  61. Montes de Oca Luna R., Wagner D. S., Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995 Nov 9;378(6553):203–206. doi: 10.1038/378203a0. [DOI] [PubMed] [Google Scholar]
  62. Moore M. S. Protein translocation: nuclear export--out of the dark. Curr Biol. 1996 Feb 1;6(2):137–140. doi: 10.1016/s0960-9822(02)00444-x. [DOI] [PubMed] [Google Scholar]
  63. Moore M., Horikoshi N., Shenk T. Oncogenic potential of the adenovirus E4orf6 protein. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11295–11301. doi: 10.1073/pnas.93.21.11295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Mosner J., Mummenbrauer T., Bauer C., Sczakiel G., Grosse F., Deppert W. Negative feedback regulation of wild-type p53 biosynthesis. EMBO J. 1995 Sep 15;14(18):4442–4449. doi: 10.1002/j.1460-2075.1995.tb00123.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Murphy R., Wente S. R. An RNA-export mediator with an essential nuclear export signal. Nature. 1996 Sep 26;383(6598):357–360. doi: 10.1038/383357a0. [DOI] [PubMed] [Google Scholar]
  66. Oliner J. D., Kinzler K. W., Meltzer P. S., George D. L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992 Jul 2;358(6381):80–83. doi: 10.1038/358080a0. [DOI] [PubMed] [Google Scholar]
  67. Oliner J. D., Pietenpol J. A., Thiagalingam S., Gyuris J., Kinzler K. W., Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993 Apr 29;362(6423):857–860. doi: 10.1038/362857a0. [DOI] [PubMed] [Google Scholar]
  68. Olson D. C., Marechal V., Momand J., Chen J., Romocki C., Levine A. J. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene. 1993 Sep;8(9):2353–2360. [PubMed] [Google Scholar]
  69. Palmer A., Rivett A. J., Thomson S., Hendil K. B., Butcher G. W., Fuertes G., Knecht E. Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. Biochem J. 1996 Jun 1;316(Pt 2):401–407. doi: 10.1042/bj3160401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Palmeri D., Malim M. H. The human T-cell leukemia virus type 1 posttranscriptional trans-activator Rex contains a nuclear export signal. J Virol. 1996 Sep;70(9):6442–6445. doi: 10.1128/jvi.70.9.6442-6445.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Pilder S., Moore M., Logan J., Shenk T. The adenovirus E1B-55K transforming polypeptide modulates transport or cytoplasmic stabilization of viral and host cell mRNAs. Mol Cell Biol. 1986 Feb;6(2):470–476. doi: 10.1128/mcb.6.2.470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Piñol-Roma S., Dreyfuss G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992 Feb 20;355(6362):730–732. doi: 10.1038/355730a0. [DOI] [PubMed] [Google Scholar]
  73. Plemper R. K., Böhmler S., Bordallo J., Sommer T., Wolf D. H. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature. 1997 Aug 28;388(6645):891–895. doi: 10.1038/42276. [DOI] [PubMed] [Google Scholar]
  74. Reifenberger G., Liu L., Ichimura K., Schmidt E. E., Collins V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 1993 Jun 15;53(12):2736–2739. [PubMed] [Google Scholar]
  75. Rudt F., Pieler T. Cytoplasmic retention and nuclear import of 5S ribosomal RNA containing RNPs. EMBO J. 1996 Mar 15;15(6):1383–1391. [PMC free article] [PubMed] [Google Scholar]
  76. Sarnow P., Hearing P., Anderson C. W., Halbert D. N., Shenk T., Levine A. J. Adenovirus early region 1B 58,000-dalton tumor antigen is physically associated with an early region 4 25,000-dalton protein in productively infected cells. J Virol. 1984 Mar;49(3):692–700. doi: 10.1128/jvi.49.3.692-700.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Sarnow P., Ho Y. S., Williams J., Levine A. J. Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell. 1982 Feb;28(2):387–394. doi: 10.1016/0092-8674(82)90356-7. [DOI] [PubMed] [Google Scholar]
  78. Shaulsky G., Ben-Ze'ev A., Rotter V. Subcellular distribution of the p53 protein during the cell cycle of Balb/c 3T3 cells. Oncogene. 1990 Nov;5(11):1707–1711. [PubMed] [Google Scholar]
  79. Shaulsky G., Goldfinger N., Tosky M. S., Levine A. J., Rotter V. Nuclear localization is essential for the activity of p53 protein. Oncogene. 1991 Nov;6(11):2055–2065. [PubMed] [Google Scholar]
  80. Simos G., Hurt E. C. Nucleocytoplasmic transport: factors and mechanisms. FEBS Lett. 1995 Aug 1;369(1):107–112. doi: 10.1016/0014-5793(95)00674-x. [DOI] [PubMed] [Google Scholar]
  81. Stutz F., Neville M., Rosbash M. Identification of a novel nuclear pore-associated protein as a functional target of the HIV-1 Rev protein in yeast. Cell. 1995 Aug 11;82(3):495–506. doi: 10.1016/0092-8674(95)90438-7. [DOI] [PubMed] [Google Scholar]
  82. Walker K. K., Levine A. J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15335–15340. doi: 10.1073/pnas.93.26.15335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Wen W., Meinkoth J. L., Tsien R. Y., Taylor S. S. Identification of a signal for rapid export of proteins from the nucleus. Cell. 1995 Aug 11;82(3):463–473. doi: 10.1016/0092-8674(95)90435-2. [DOI] [PubMed] [Google Scholar]
  84. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  85. Wójcik C., Paweletz N., Schroeter D. Localization of proteasomal antigens during different phases of the cell cycle in HeLa cells. Eur J Cell Biol. 1995 Oct;68(2):191–198. [PubMed] [Google Scholar]
  86. Wójcik C., Schroeter D., Wilk S., Lamprecht J., Paweletz N. Ubiquitin-mediated proteolysis centers in HeLa cells: indication from studies of an inhibitor of the chymotrypsin-like activity of the proteasome. Eur J Cell Biol. 1996 Nov;71(3):311–318. [PubMed] [Google Scholar]
  87. Xiao Z. X., Chen J., Levine A. J., Modjtahedi N., Xing J., Sellers W. R., Livingston D. M. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995 Jun 22;375(6533):694–698. doi: 10.1038/375694a0. [DOI] [PubMed] [Google Scholar]
  88. Yew P. R., Berk A. J. Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. Nature. 1992 May 7;357(6373):82–85. doi: 10.1038/357082a0. [DOI] [PubMed] [Google Scholar]
  89. Zauberman A., Flusberg D., Haupt Y., Barak Y., Oren M. A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res. 1995 Jul 25;23(14):2584–2592. doi: 10.1093/nar/23.14.2584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Zhu H., Shen Y., Shenk T. Human cytomegalovirus IE1 and IE2 proteins block apoptosis. J Virol. 1995 Dec;69(12):7960–7970. doi: 10.1128/jvi.69.12.7960-7970.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES