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.
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M3 - Article
C2 - 9699674
AN - SCOPUS:0032146730
VL - 58
SP - 3415
EP - 3422
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 15
ER -