Abstract
The epidermal growth factor-like receptor tyrosine kinase (ErbB) family is frequently overexpressed in a variety of human carcinomas, including breast cancer. To assist in characterizing the role of ErbB-4 in breast cancer, we generated three specific hammerhead ribozymes targeted to the ErbB-4 mRNA. These ribozymes, Rz6, Rz21, and Rz29, efficiently catalyzed the specific cleavage of ErbB-4 message in a cell-free system. We demonstrated that the neuregulin-induced mitogenic effect was abolished in ribozyme Rz29- and Rz6-transfected 32D/ErbB-4 cells. Inhibition of mitogenesis was characterized by ribozyme-mediated down-regulation of ErbB-4 expression. In addition, we provide the first evidence that different threshold levels of ErbB-4 expression and activation correlate with different responses to neuregulin stimulation. High levels of ErbB-4 expression, phosphorylation, and homodimerization are necessary for neuregulin-stimulated, interleukin 3- independent cell proliferation in the 32D/E4 cells. In the case of Rz29- transfected 32D/E4 cells, low levels of ErbB-4 expression allowed neuregulin- induced phosphorylation but were insufficient to couple the activated receptor to cellular signaling. Furthermore, expression of the functional ErbB-4 ribozyme in T47I) human breast carcinoma cells led to a down- regulation of endogenous ErbB-4 expression and a reduction of anchorage- independent colony formation. These studies support the use of ErbB-4 ribozymes to define the role of ErbB-4 receptors in human cancers.
| Original language | English |
|---|---|
| Pages (from-to) | 3415-3422 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 58 |
| Issue number | 15 |
| State | Published - Aug 1 1998 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
ErbB-4 ribozymes abolish neuregulin-induced mitogenesis. / Tang, Careen K.; Goldstein, David J.; Payne, Jennifer; Czubayko, Frank; Alimandi, Maurizio; Wang, Ling Mei; Pierce, Jacalyn H.; Lippman, Marc E.
In: Cancer Research, Vol. 58, No. 15, 01.08.1998, p. 3415-3422.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ErbB-4 ribozymes abolish neuregulin-induced mitogenesis
AU - Tang, Careen K.
AU - Goldstein, David J.
AU - Payne, Jennifer
AU - Czubayko, Frank
AU - Alimandi, Maurizio
AU - Wang, Ling Mei
AU - Pierce, Jacalyn H.
AU - Lippman, Marc E
PY - 1998/8/1
Y1 - 1998/8/1
N2 - The epidermal growth factor-like receptor tyrosine kinase (ErbB) family is frequently overexpressed in a variety of human carcinomas, including breast cancer. To assist in characterizing the role of ErbB-4 in breast cancer, we generated three specific hammerhead ribozymes targeted to the ErbB-4 mRNA. These ribozymes, Rz6, Rz21, and Rz29, efficiently catalyzed the specific cleavage of ErbB-4 message in a cell-free system. We demonstrated that the neuregulin-induced mitogenic effect was abolished in ribozyme Rz29- and Rz6-transfected 32D/ErbB-4 cells. Inhibition of mitogenesis was characterized by ribozyme-mediated down-regulation of ErbB-4 expression. In addition, we provide the first evidence that different threshold levels of ErbB-4 expression and activation correlate with different responses to neuregulin stimulation. High levels of ErbB-4 expression, phosphorylation, and homodimerization are necessary for neuregulin-stimulated, interleukin 3- independent cell proliferation in the 32D/E4 cells. In the case of Rz29- transfected 32D/E4 cells, low levels of ErbB-4 expression allowed neuregulin- induced phosphorylation but were insufficient to couple the activated receptor to cellular signaling. Furthermore, expression of the functional ErbB-4 ribozyme in T47I) human breast carcinoma cells led to a down- regulation of endogenous ErbB-4 expression and a reduction of anchorage- independent colony formation. These studies support the use of ErbB-4 ribozymes to define the role of ErbB-4 receptors in human cancers.
AB - The epidermal growth factor-like receptor tyrosine kinase (ErbB) family is frequently overexpressed in a variety of human carcinomas, including breast cancer. To assist in characterizing the role of ErbB-4 in breast cancer, we generated three specific hammerhead ribozymes targeted to the ErbB-4 mRNA. These ribozymes, Rz6, Rz21, and Rz29, efficiently catalyzed the specific cleavage of ErbB-4 message in a cell-free system. We demonstrated that the neuregulin-induced mitogenic effect was abolished in ribozyme Rz29- and Rz6-transfected 32D/ErbB-4 cells. Inhibition of mitogenesis was characterized by ribozyme-mediated down-regulation of ErbB-4 expression. In addition, we provide the first evidence that different threshold levels of ErbB-4 expression and activation correlate with different responses to neuregulin stimulation. High levels of ErbB-4 expression, phosphorylation, and homodimerization are necessary for neuregulin-stimulated, interleukin 3- independent cell proliferation in the 32D/E4 cells. In the case of Rz29- transfected 32D/E4 cells, low levels of ErbB-4 expression allowed neuregulin- induced phosphorylation but were insufficient to couple the activated receptor to cellular signaling. Furthermore, expression of the functional ErbB-4 ribozyme in T47I) human breast carcinoma cells led to a down- regulation of endogenous ErbB-4 expression and a reduction of anchorage- independent colony formation. These studies support the use of ErbB-4 ribozymes to define the role of ErbB-4 receptors in human cancers.
UR - http://www.scopus.com/inward/record.url?scp=0032146730&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032146730&partnerID=8YFLogxK
M3 - Article
C2 - 9699674
AN - SCOPUS:0032146730
VL - 58
SP - 3415
EP - 3422
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 15
ER -