Growth hormone (GH) binding and effects of GH analogs in transgenic mice
- Southern Illinois Univ., Carbondale, IL (United States)
- UBA-CONICET, Buenos Aires (Argentina); and others
Overexpression of human (h) or bovine (b) growth hormone (GH) in transgenic mice is associated with marked (2- to 12-fold) and significant increase in hepatic binding of GH and prolactin (PRL). This is due to an increase in the number of GH and PRL receptors (GHR, PRLR) per mg of microsomal protein without changes in binding affinity. Comparison of results obtained in transgenic animals expressing bGH with a mouse metallothionein (MT) or a rat phosphoenolpyruvate carboxykinase (PEPCK) promoter suggests that effects of bGH on hepatic GHR and PRLR do not require GH overexpression during fetal life and, within the dose range tested, the effects on PRLR are not dose dependent. The increase in hepatic GHR was accompanied by significant increases in plasma GH-binding protein (GHBP) and in mean residence time of injected GH. Thus life-long elevation of peripheral GH levels alters the availability of both free GH and GHR. Site-directed in vitro mutagenesis was used to produce hGH and bGH analogs mutated within one of the sites involved in binding to GHR and PRLR. Mutating hGH to produce amino acid identity with bGH at Position 11, 18 (within Helix 1), 57, or 60 (within the loop between Helix 1 and 2) did not affect binding to GHR in vitro, or somatotropic activity in transgenic mice in vivo but reduced lactogenic activity in Nb{sub 2} cells by 22%-45%. Mutations of bGH designed to produce amino acid identity with hGH at one to four of the corresponding positions in the bGH molecule did not interfere with binding to GHR or somatotropic activity in vivo, and failed to produce significant binding to PRLR but resulted in alterations in the effects on the hypothalamic and anterior pituitary function in transgenic mice. Apparently region(s) outside the domains examined are essential for lactogenic activity of hGH, and different portions of the GH molecule are responsible for its diverse actions in vivo. 35 refs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 466614
- Journal Information:
- Proceedings of the Society for Experimental Biology and Medicine, Vol. 206; Other Information: PBD: 1994
- Country of Publication:
- United States
- Language:
- English
Similar Records
Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment
Growth hormone induction of lactogenic receptors at intracellular sites in male rat liver
Related Subjects
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
STH
RECEPTORS
GENE REGULATION
STRUCTURE-ACTIVITY RELATIONSHIPS
MUTAGENESIS
AMINO ACID SEQUENCE
TRANSCRIPTION
BIOCHEMICAL REACTION KINETICS
GENE MUTATIONS
BIOSYNTHESIS
LTH
PROTEINS
IODINE 125
RADIONUCLIDE KINETICS
TRANSGENIC MICE
LIVER
METALLOTHIONEIN
PHOSPHOENOLPYRUVATE
CATTLE
RATS