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Synergistic stimulation of DNA synthesis by bradykinin and vasopressin in swiss 3T3 cells
Author(s) -
Kiehne Karlheinz,
Rozengurt Enrique
Publication year - 1994
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1041600313
Subject(s) - bradykinin , dna synthesis , vasopressin , tyrosine phosphorylation , protein kinase c , tyrosine kinase , bradykinin receptor , phosphorylation , stimulation , biology , receptor , biochemistry , chemistry , medicine , endocrinology , dna
Vasopressin and bradykinin bind to receptors coupled to GTP‐binding proteins and rapidly induce polyphosphoinositide breakdown leading to Ca 2+ mobilization and activation of protein kinase C. Both peptides are known to induce mitogenesis in the presence of growth factors that act through receptors with intrinsic tyrosine kinase activity. Surprisingly, addition of a combination of vaso‐pressin and bradykinin to Swiss 3T3 cells synergistically stimulates DNA synthesis in the absence of any other growth factors. This effect is induced at nanomolar concentrations of the peptides and could be inhibited by addition of specific receptor antagonists or broad spectrum neuropeptide antagonists. Bradykinin, which stimulates transient activation of protein kinase C, induces DNA synthesis in synergy with substances that cause long‐term activation of protein kinase C, like vasopression or phorbol 12, 13‐dibutyrate. Down‐regulation of protein kinase C inhibited the induction of mitogenesis by the combination of vasopressin and bradykinin, thus demonstrating the importance of long‐term activation of this enzyme for DNA synthesis. Analysis of tyrosine phosphorylated proteins of M r = 110,000–130,000 and M r = 70,000–80,000 revealed a biphasic response after stimulation with bradykinin, whereas the response induced by vasopressin declined after the initial maximum. The combination of bradykinin with vasopressin caused an enhanced and prolonged increase in tyrosine phosphorylation of these proteins as compared with the individual peptides. Inhibition of tyrosine phosphorylation by tyrphostin was paralleled by inhibition of DNA synthesis. Together, these results demonstrate synergistic stimulation of DNA synthesis by bradykinin and vasopressin via prolonged stimulation of multiple signaling pathways and imply that the interactive effects of Ca 2+ ‐mobilizing peptides on mitogenesis may be more general than previously thought. © 1994 Wiley‐Liss, Inc.