Growth hormone (GH) binding and effects of GH analogs in transgenic mice

Journal Article · Sat Dec 31 04:00:00 EST 1994 · Proceedings of the Society for Experimental Biology and Medicine

DOI:https://doi.org/10.3181/00379727-206-43740· OSTI ID:466614

Bartke, A; Steger, R W ^[1]; Turyn, D ^[2]

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1. Southern Illinois Univ., Carbondale, IL (United States)
2. 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, Journal Name: Proceedings of the Society for Experimental Biology and Medicine Vol. 206; ISSN PSEBAA; ISSN 0037-9727
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
AMINO ACID SEQUENCE
BIOCHEMICAL REACTION KINETICS
BIOSYNTHESIS
CATTLE
GENE MUTATIONS
GENE REGULATION
IODINE 125
LIVER
LTH
METALLOTHIONEIN
MUTAGENESIS
PHOSPHOENOLPYRUVATE
PROTEINS
RADIONUCLIDE KINETICS
RATS
RECEPTORS
STH
STRUCTURE-ACTIVITY RELATIONSHIPS
TRANSCRIPTION
TRANSGENIC MICE