Cancer Letters
Volume 228, Issue 1 , Pages 21-27, 18 October 2005

MDM2 as MYCN transcriptional target: Implications for neuroblastoma pathogenesis

  • Andrew Slack

      Affiliations

    • Department of Pediatrics, Texas Children's Cancer Center and Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    • ,
  • Guillermina Lozano

      Affiliations

    • Department of Molecular Genetics, Section of Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
    • ,
  • Jason M. Shohet

      Affiliations

    • Department of Pediatrics, Texas Children's Cancer Center and Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    • Corresponding Author InformationCorresponding author. Tel.: +31 20 5666592.

Received 15 December 2004; accepted 12 January 2005.

Abstract 

MYCN amplification is associated with an exceptionally poor prognosis in neuroblastoma. Furthermore, the crucial effectors of MYCN responsible for this aggressive subset of neuroblastoma await characterization. A critical negative regulator of the p53 tumor suppressor, MDM2, has been recently characterized in neuroblastoma cell lines as a transcriptional target of MYCN. Targeted inhibition of MYCN results in reduced MDM2 expression levels, with concomitant stabilization of p53 and stimulation of apoptosis in MYCN amplified neuroblastoma cell lines. These data suggest the possibility that MYCN-driven expression of MDM2 might play a role in counterbalancing the p53-dependent apoptotic pathways concurrently stimulated by over expression of MYC proteins. Mouse models of lymphoma have demonstrated that MDM2 expression, with decreased p53 activity, is critical for complete MYCC driven tumorigenesis. Our data suggest that a similar situation may apply for MYCN in neuroblastoma. Strategies for pharmacologic and genetic inhibition of MDM2 may prove to be an important new therapeutic approach in neuroblastoma.

Keywords: MYCN, MDM2, Apoptosis, Neuroblastoma, p53

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

PII: S0304-3835(05)00350-2

doi:10.1016/j.canlet.2005.01.050

Cancer Letters
Volume 228, Issue 1 , Pages 21-27, 18 October 2005

Article Tools

* Image Usage & Resolution