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Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells.

Publication ,  Journal Article
Sui, X; Shin, S; Zhang, R; Firozi, PF; Yang, L; Abbruzzese, JL; Reddy, SAG
Published in: Oncogene
February 5, 2009

There is emerging evidence that the oncogenic potential of hdm2 (human and/or murine double minute-2 protein) stems not only from its ability to counteract tumor suppressor p53 but also from its less understood p53-independent functions. Surprisingly, little is known about the role and regulation of hdm2 in pancreatic tumors, a large proportion (50-75%) of which contain mutant p53. In this study, we determined that hdm2 was expressed in a Ras-signaling-dependent manner in various pancreatic cancer cell lines. As p53 was mutated and inactive in these cells, the expression of hdm2 was seemingly redundant. Indeed, the proliferation and survival of cell lines such as Panc-1 and Panc-28 could be inhibited by PRIMA-1 (mutant p53 activator) but not by Nutlin-3 (inhibitor of the hdm2-p53 interaction). Unexpectedly, however, the proliferation of both cell lines was strongly inhibited by hdm2-specific RNAi. Our data also revealed cyclin D1, c-Jun and c-Myc to be novel targets of hdm2 and suggested that they might mediate hdm2's role in cellular proliferation and/or survival. We conclude from our results that hdm2 is expressed in pancreatic cancer cells as a result of activated Ras signaling, and that it regulates cellular proliferation and the expression of three novel target genes by p53-independent mechanisms.

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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

February 5, 2009

Volume

28

Issue

5

Start / End Page

709 / 720

Location

England

Related Subject Headings

  • raf Kinases
  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Proto-Oncogene Proteins c-mdm2
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mutant Proteins
  • MAP Kinase Kinase Kinases
  • Humans
  • Genes, ras
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sui, X., Shin, S., Zhang, R., Firozi, P. F., Yang, L., Abbruzzese, J. L., & Reddy, S. A. G. (2009). Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells. Oncogene, 28(5), 709–720. https://doi.org/10.1038/onc.2008.423
Sui, X., S. Shin, R. Zhang, P. F. Firozi, L. Yang, J. L. Abbruzzese, and S. A. G. Reddy. “Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells.Oncogene 28, no. 5 (February 5, 2009): 709–20. https://doi.org/10.1038/onc.2008.423.
Sui X, Shin S, Zhang R, Firozi PF, Yang L, Abbruzzese JL, et al. Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells. Oncogene. 2009 Feb 5;28(5):709–20.
Sui, X., et al. “Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells.Oncogene, vol. 28, no. 5, Feb. 2009, pp. 709–20. Pubmed, doi:10.1038/onc.2008.423.
Sui X, Shin S, Zhang R, Firozi PF, Yang L, Abbruzzese JL, Reddy SAG. Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells. Oncogene. 2009 Feb 5;28(5):709–720.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

February 5, 2009

Volume

28

Issue

5

Start / End Page

709 / 720

Location

England

Related Subject Headings

  • raf Kinases
  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Proto-Oncogene Proteins c-mdm2
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Mutant Proteins
  • MAP Kinase Kinase Kinases
  • Humans
  • Genes, ras