Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors

Ellen Q. Ingalla, Jamie K. Miller, Jessica H. Wald, Heather C. Workman, Rouminder P. Kaur, Lily Yen, William H D Fry, Alexander D Borowsky, Lawrence J T Young, Colleen A Sweeney, Kermit L Carraway

Research output: Contribution to journalArticle

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Abstract

The ErbB2 and ErbB3 receptor tyrosine kinases act synergistically to promote cellular properties associated with tumor development. Previous studies indicate that endogenous ErbB3 protein is markedly elevated in mouse mammary tumors induced by transgenic ErbB2 overexpression. However, this occurs in the absence of elevated ErbB3 transcript, indicating that post-transcriptional regulatory mechanisms play crucial roles in suppressing ErbB3 protein in normal tissue. Our previous studies also demonstrate that protein levels of Nrdp1, an E3 ubiquitin ligase that targets ErbB3 for degradation, are markedly suppressed in tumors from ErbB2 transgenic animals relative to normal tissue. Here we demonstrate that transgenic expression of Nrdp1 cDNA in the mouse mammary gland is not sufficient to suppress elevated ErbB3 levels or tumor initiation and growth in ErbB2 transgenic mice. Unexpectedly, Nrdp1 protein is absent in tumors from Nrdp1/ErbB2 bigenic mice, and real time PCR analysis indicates that Nrdp1 protein levels are suppressed post-transcriptionally. Nrdp1 protein is more resistant to proteasome-dependent degradation when exogenously expressed in cultured MCF10A nontransformed human breast epithelial cells than in breast tumor cells. These observations indicate that mammary tumors use potent post-transcriptional mechanisms to suppress Nrdp1 protein levels and that protein destabilization may play a central role in Nrdp1 loss in tumors.

Original languageEnglish (US)
Pages (from-to)28691-28697
Number of pages7
JournalJournal of Biological Chemistry
Volume285
Issue number37
DOIs
StatePublished - Sep 10 2010

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Tumors
Breast Neoplasms
Proteins
Neoplasms
Tissue
Degradation
Genetically Modified Animals
Ubiquitin-Protein Ligases
Receptor Protein-Tyrosine Kinases
Proteasome Endopeptidase Complex
Human Mammary Glands
Transgenic Mice
Real-Time Polymerase Chain Reaction
Animals
Breast
Complementary DNA
Epithelial Cells
Cells
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors. / Ingalla, Ellen Q.; Miller, Jamie K.; Wald, Jessica H.; Workman, Heather C.; Kaur, Rouminder P.; Yen, Lily; Fry, William H D; Borowsky, Alexander D; Young, Lawrence J T; Sweeney, Colleen A; Carraway, Kermit L.

In: Journal of Biological Chemistry, Vol. 285, No. 37, 10.09.2010, p. 28691-28697.

Research output: Contribution to journalArticle

Ingalla, Ellen Q. ; Miller, Jamie K. ; Wald, Jessica H. ; Workman, Heather C. ; Kaur, Rouminder P. ; Yen, Lily ; Fry, William H D ; Borowsky, Alexander D ; Young, Lawrence J T ; Sweeney, Colleen A ; Carraway, Kermit L. / Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 37. pp. 28691-28697.
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