Ciliary neurotrophic factor induces down-regulation of its receptor and desensitization of signal transduction pathways in vivo: non-equivalence with pharmacological activity.
Despite the widespread use of polypeptide growth factors as pharmacological agents, little is known about the extent to which these molecules regulate their cognate cell surface receptors and signal transduction pathways in vivo. We have addressed this issue with respect to the neurotrophic molecule ciliary neurotrophic factor (CNTF). Administration of CNTF in vivo resulted in modest decreases in levels of CNTFRalpha mRNA and protein in skeletal muscle. CNTF causes the rapid tyrosine phosphorylation of LIFRbeta and gp130 and the induction of the immediate-early gene, tis11; injection of CNTF 3-7 h after an initial exposure failed to re-stimulate these immediate-early responses, suggesting a biochemical desensitization to CNTF not accounted for by decreased receptor protein. To determine whether the desensitization of immediate-early responses caused by CNTF resulted in a functional desensitization, we compared the efficacy of multiple daily injections versus a single daily dose of CNTF in preventing the denervation-induced atrophy of skeletal muscle. Surprisingly, injections of CNTF every 6 h, which falls within the putative refractory period for biochemical responses, resulted in efficacy equal to or greater than injections once daily. These results suggest that although much of the CNTF signal transduction machinery is down-regulated with frequent CNTF dosing, biological signals continue to be recognized and interpreted by the cell.
DiStefano
P S
PS
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591-6707, USA.
Boulton
T G
TG
Stark
J L
JL
Zhu
Y
Y
Adryan
K M
KM
Ryan
T E
TE
Lindsay
R M
RM
D000818:Animals; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051816:Tristetraprolin
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D051816:Tristetraprolin; C497554:Zfp36 protein, rat