Post-transcriptional mechanisms contribute to the suppression of the ErbB3 negative regulator protein Nrdp1 in mammary tumors.
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.
Ingalla
Ellen Q
EQ
University of California Davis Cancer Center, Sacramento, California 95817, USA.
Miller
Jamie K
JK
Wald
Jessica H
JH
Workman
Heather C
HC
Kaur
Rouminder P
RP
Yen
Lily
L
Fry
William H D
WH
Borowsky
Alexander D
AD
Young
Lawrence J T
LJ
Sweeney
Colleen
C
Carraway
Kermit L
KL
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D055550:Protein Stability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D044767:Ubiquitin-Protein Ligases; C452580:RNF41 protein, human; C435904:Rnf41 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse