Location of Repository

The mechanisms of regulation of Hdm2 protein level by serum growth factors

By Anna Phillips, Chris J. Jones and Jeremy P. Blaydes

Abstract

Cell cycle progression in response to serum growth factors is dependent on the expression of functional Hdm2 (Mdm2), which inhibits p53-dependent transcription of anti-proliferative genes. In a well characterised non-transformed human fibroblast model, growth factors induce the expression of Hdm2 with rapid kinetics. Here we dissect the mechanistic basis for this critical response. In contrast to previous studies in which components of the growth factor signalling pathways were overexpressed, hdm2 mRNA expression is not induced with immediate-early kinetics in these cells. Rather, the elevated Hdm2 protein levels which follow growth factor stimulation are primarily a consequence of phosphatidylinositol-3 kinase-dependent stabilisation of the Hdm2 protein combined with a global increase in protein synthesis.<br/><br/

Topics: RB, RC0254, QH301
Year: 2006
OAI identifier: oai:eprints.soton.ac.uk:26524
Provided by: e-Prints Soton

Suggested articles

Preview

Citations

  1. (1995). A functional p53-responsive intronic promoter is contained within the human mdm2 gene.
  2. (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.
  3. (1999). Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes.
  4. (2001). Human telomerase reverse transcriptase-immortalized MRC-5 and HCA2 human fibroblasts are fully permissive for human cytomegalovirus.
  5. (2004). In vivo activation of the p53 pathway by smallmolecule antagonists of MDM2.
  6. (1997). Induction of Mdm2 and enhancement of cell survival by bFGF.
  7. (1993). Mapping of the p53 and mdm2 interaction domains.
  8. (2003). mdm2 Is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation.
  9. (2000). MDM2--master regulator of the p53 tumor suppressor protein.
  10. (2005). MEK-ERK signaling controls Hdm2 oncoprotein expression by regulating hdm2 mRNA export to the cytoplasm.
  11. (1999). Messenger RNA translation state: the second dimension of high-throughput expression screening.
  12. (2000). Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF.
  13. (1994). p53 and mdm2 are expressed independently during cellular proliferation.
  14. (2003). p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha positive breast cancer cells.
  15. (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53.
  16. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53.
  17. (1999). Role of two upstream open reading frames in the translational control of oncogene mdm2.
  18. (2004). Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation.
  19. (2000). Surfing the p53 network.
  20. (1998). The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2.
  21. (1998). The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways.
  22. (1998). The proliferation of normal human fibroblasts is dependent upon negative regulation of p53 function by mdm2.
  23. (1993). Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.