Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

Abstract

Although previous studies suggested that the tumorigenicity of mouse double minute 2 (MDM2) was due to its negative regulation of p53, the p53-independent interactions may be equally as important. During recent studies utilizing MDM2 inhibitors, we noted that E2F transcription factor 1 (E2F1) was downregulated upon inhibition of MDM2, regardless of the p53 status of the cancer. The present study investigated the mechanisms responsible for the MDM2-mediated increase in E2F1 expression. MDM2 prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination. MDM2 displaces SCFSKP2, the E2F1 E3 ligase. Direct binding between MDM2 and E2F1 is necessary for the negative effects of MDM2 on E2F1 ubiquitination, and deletion of the MDM2 nuclear localization signal does not result in loss of the ability to increase the E2F1 protein level. The downregulation of E2F1 upon MDM2 inhibition was not due to either pRB or p14Arf. In addition, E2F1 was responsible for at least part of the inhibition of cell proliferation induced by MDM2 knockdown. In conclusion, the present study provides evidence that stabilization of the E2F1 protein is likely another p53-independent component of MDM2-mediated tumorigenesis. More knowledge about the MDM2–E2F1 interaction may be helpful in developing novel anticancer therapies.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Abbreviations

MDM2:

mouse double minute 2

Oligo:

oligonucleotides

AS:

antisense oligonucleotide

ASM:

mismatch control oligonucleotide

E2F1:

E2F transcription factor 1

References

  • Arakawa Y, Kajino K, Kano S, Tobita H, Hayashi J, Yasen M, Moriyama M, Arakawa Y and Hino O . (2004). Biochem. Biophys. Res. Commun., 322, 297–302.

  • Bardos JI, Chau NM and Ashcroft M . (2004). Mol. Cell. Biol., 24, 2905–2914.

  • Bartel F, Harris LC, Wurl P and Taubert H . (2004). Mol. Cancer Res., 2, 29–35.

  • Baudino TA, Maclean KH, Brennan J, Parganas E, Yang C, Aslanian A, Lees JA, Sherr CJ, Roussel MF and Cleveland JL . (2003). Mol. Cell, 11, 905–914.

  • Bell LA and Ryan KM . (2004). Cell Death Differ., 11, 137–142.

  • Bond GL, Hu W and Levine AJ . (2005). Curr. Cancer Drug Targets, 5, 3–8.

  • Campanero MR and Flemington EK . (1997). Proc. Natl. Acad. Sci. USA, 94, 2221–2226.

  • Chen J, Marechal V and Levine AJ . (1993). Mol. Cell. Biol., 13, 4107–4114.

  • Cordon-Cardo C, Latres E, Drobnjak M, Oliva MR, Pollack D, Woodruff JM, Marechal V, Chen J, Brennan MF and Levine AJ . (1994). Cancer Res., 54, 794–799.

  • Datta A, Nag A and Raychaudhuri P . (2002). Mol. Cell. Biol., 22, 8398–8408.

  • Deb SP . (2003). Mol. Cancer Res., 1, 1009–1016.

  • Fakharzadeh SS, Trusko SP and George DL . (1991). EMBO J., 10, 1565–1569.

  • Freedman DA and Levine AJ . (1998). Mol. Cell. Biol., 18, 7288–7293.

  • Fuchs SY, Adler V, Buschmann T, Wu X and Ronai Z . (1998). Oncogene, 17, 2543–2547.

  • Girnita L, Girnita A and Larsson O . (2003). Proc. Natl. Acad. Sci. USA, 100, 8247–8252.

  • Gorgoulis VG, Zacharatos P, Mariatos G, Kotsinas A, Bouda M, Kletsas D, Asimacopoulos PJ, Agnantis N, Kittas C and Papavassiliou AG . (2002). J. Pathol., 198, 142–156.

  • Hsieh JK, Chan FS, O'Connor DJ, Mittnacht S, Zhong S and Lu X . (1999). Mol. Cell, 3, 181–193.

  • Imai MA, Oda Y, Oda M, Nakanishi I and Kawahara E . (2004). J. Cancer Res. Clin. Oncol., 130, 320–326.

  • Iwakuma T and Lozano G . (2003). Mol. Cancer Res., 1, 993–1000.

  • Jiang Y, Saavedra HI, Holloway MP, Leone G and Altura RA . (2004). J. Biol. Chem., 279, 40511–40520.

  • Jin Y, Lee H, Zeng SX, Dai MS and Lu H . (2003). EMBO J., 22, 6365–6377.

  • Jones SN, Roe AE, Donehower LA and Bradley A . (1995). Nature, 378, 206–208.

  • Kinyamu HK and Archer TK . (2003). Mol. Cell. Biol., 23, 5867–5881.

  • Kovesdi I, Reichel R and Nevins JR . (1986). Cell, 45, 219–228.

  • La Thangue NB . (2003). Nat. Cell Biol., 5, 587–589.

  • Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK and Thorgeirsson SS . (2004). Nat. Genet., 36, 1306–1311.

  • Li M, Brooks CL, Wu-Baer F, Chen D, Baer R and Gu W . (2003). Science, 302, 1972–1975.

  • Liang H, Atkins H, Abdel-Fattah R, Jones SN and Lunec J . (2004). Gene, 338, 217–223.

  • Lin HK, Wang L, Hu YC, Altuwaijri S and Chang C . (2002). EMBO J., 21, 4037–4048.

  • Lin WC, Lin FT and Nevins JR . (2001). Genes Dev., 15, 1833–1844.

  • Logan N, Delavaine L, Graham A, Reilly C, Wilson J, Brummelkamp TR, Hijmans EM, Bernards R and La Thangue NB . (2004). Oncogene, 23, 5138–5150.

  • Louie MC, Zou JX, Rabinovich A and Chen HW . (2004). Mol. Cell. Biol., 24, 5157–5171.

  • Marti A, Wirbelauer C, Scheffner M and Krek W . (1999). Nat. Cell Biol., 1, 14–19.

  • Martin K, Trouche D, Hagemeier C, Sorensen TS, La Thangue NB and Kouzarides T . (1995). Nature, 375, 691–694.

  • Meek DW and Knippschild U . (2003). Mol. Cancer Res., 1, 1017–1026.

  • Minsky N and Oren M . (2004). Mol. Cell, 16, 631–639.

  • Momand J, Zambetti GP, Olson DC, George D and Levine AJ . (1992). Cell, 69, 1237–1245.

  • Mundle SD and Saberwal G . (2003). FASEB J., 17, 569–574.

  • Onda M, Nagai H, Yoshida A, Miyamoto S, Asaka S, Akaishi J, Takatsu K, Nagahama M, Ito K, Shimizu K and Emi M . (2004). J. Hum. Genet., 49, 312–318.

  • Rayburn ER, Zhang RW, He J and Wang H . (2005). Curr. Cancer Drug Targets, 5, 27–42.

  • Stanelle J, Tu-Rapp H and Putzer BM . (2005). Cell Death Differ., 2, 347–357.

  • Steinman HA, Burstein E, Lengner C, Gosselin J, Pihan G, Duckett CS and Jones SN . (2004). J. Biol. Chem., 279, 4877–4886.

  • Sun P, Dong P, Dai K, Hannon GJ and Beach D . (1998). Science, 282, 2270–2272.

  • Trimarchi JM and Lees JA . (2002). Nat. Rev. Mol. Cell Biol., 3, 11–20.

  • Vargas DA, Takahashi S and Ronai Z . (2003). Adv. Cancer Res., 89, 1–34.

  • Wang H, Nan L, Yu D, Agrawal S and Zhang R . (2001). Clin. Cancer Res., 7, 3613–3624.

  • Wang H, Nan L, Yu D, Lindsey JR, Agrawal S and Zhang R . (2002). Mol. Med., 8, 185–198.

  • Wang H, Oliver P, Zhang Z, Agrawal S and Zhang R . (2003a). Ann. NY Acad. Sci., 1002, 217–235.

  • Wang H, Yu D, Agrawal S and Zhang R . (2003b). Prostate, 54, 194–205.

  • Wang H, Zeng X, Oliver P, Le LP, Chen J, Chen L, Zhou W, Agrawal S and Zhang R . (1999). Int. J. Oncol., 15, 653–660.

  • Wikonkal NM, Remenyik E, Knezevic D, Zhang W, Liu M, Zhao H, Berton TR, Johnson DG and Brash DE . (2003). Nat. Cell Biol., 5, 655–660.

  • Yamazaki K, Yajima T, Nagao T, Shinkawa H, Kondo F, Hanami K, Asoh A, Sugano I and Ishida Y . (2003). Pathol. Res. Pract., 199, 23–28.

  • Zhang R and Wang H . (2000). Curr. Pharm. Des., 6, 393–416.

  • Zhang R, Wang H and Agrawal S . (2005). Curr. Cancer Drug Targets, 5, 43–50.

  • Zhang Z, Li M, Wang H, Agrawal S and Zhang R . (2003). Proc. Natl. Acad. Sci. USA, 100, 11636–11641.

  • Zhang Z, Wang H, Li M, Agrawal S, Chen X and Zhang R . (2004a). J. Biol. Chem., 279, 16000–16006.

  • Zhang Z, Wang H, Prasad G, Li M, Yu D, Bonner JA, Agrawal S and Zhang R . (2004b). Clin. Cancer Res., 10, 1263–1273.

  • Zhang Z and Zhang R . (2005). Curr. Cancer Drug Targets, 5, 9–20.

Download references

Acknowledgements

We thank Dr Jian-He Wu for excellent technical assistance and Drs Xinbin Chen and Robert B Diasio for helpful discussions. HW was partly supported by funds for the Cancer Pharmacology Laboratory from the UAB Comprehensive Cancer Center. This work was supported by grants from the National Institutes of Health/National Cancer Institute (to RZ, Grant number CA 80698 and CA 112029). ZZ was supported in part by a post-doctoral fellowship from the USA Department of Defense Prostate Cancer Research Program (Grant number W81XWH-04-1-0845).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ruiwen Zhang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhang, Z., Wang, H., Li, M. et al. Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway. Oncogene 24, 7238–7247 (2005). https://doi.org/10.1038/sj.onc.1208814

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208814

Keywords

  • MDM2
  • E2F1
  • ubiquitination
  • protein–protein interaction

This article is cited by

Search

Quick links