Growth hormone replacement therapy in elderly growth hormone ...
MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and...
-
Upload
jack-doherty -
Category
Documents
-
view
218 -
download
0
Transcript of MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and...
![Page 1: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/1.jpg)
MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY
LECTURE 7 - Mechanism of action of growth hormone and prolactin
Growth hormone: general actions; receptor; signal transduction; IGFs
Prolactin: actions on mammary gland; other actions; receptor; signal transduction
Mechanism of action of cytokines
![Page 2: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/2.jpg)
The GH-IGF-Somatic axis
![Page 3: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/3.jpg)
GH RECEPTOR
• First cloned (as cDNA) from rabbit and then human liver (Leung et al 1987)
signal
extracellular
transmembrane
intracellular0 247 620
Shown to be the “real” receptor by specificity, and absence in patients with Laron dwarfism
![Page 4: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/4.jpg)
Cytokine receptors
![Page 5: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/5.jpg)
OVINE GH-RECEPTOR HOMOLOGY MODEL
![Page 6: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/6.jpg)
![Page 7: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/7.jpg)
ReceptorReceptor
Intracellular actions
GH-RECEPTOR INTERACTION
![Page 8: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/8.jpg)
JAK Kinases
Soluble tyrosine protein kinases, first named “just another kinase”. Subsequently “janus kinases” (because two apparent binding sites for ATP)
JAK1JAK2JAK3Tyk
![Page 9: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/9.jpg)
GH Receptor and jak2
From: Herrington & Carter-Su (2001)
![Page 10: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/10.jpg)
GH signalling
From: Herrington & Carter-Su (2001)
![Page 11: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/11.jpg)
STAT = signal transduction and activation of transcription
STAT1-STAT5
In 3T3-F442A cells use of antisense knock-out of JAK2 or STAT5 eliminates GH actions. Depletion of MAPK pathway and p70s6 kinase pathway does not
![Page 12: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/12.jpg)
Regulation of GH receptor–JAK2 signaling
From: Herrington & Carter-Su (2001)
![Page 13: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/13.jpg)
The GH-IGF-Somatic axis
![Page 14: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/14.jpg)
THE SULPHATION FACTOR/SOMATOMEDIN/IGF HYPOTHESIS
Inject hypophysectomized rat with GH: induces growth and metabolism of cartilage (including incorporation of 35SO4 into cartilage)
Incubate cartilage from hypox rat with serum from hypox rat + GH - no stimulation of cartilage metabolism
Incubate cartilage from hypox rat with serum from GH-treated rat -stimulation of cartilage metabolism
SO GH treatment leads to production of a factor in serum which can stimulate cartilage metabolism and growth
![Page 15: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/15.jpg)
Insulin-like growth factor I and II
IGF I IGF II
Somatomedins
Non-suppressible-insulin-like-activity (NSILA)
Multiplication stimulating activity (MSA)
![Page 16: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/16.jpg)
Sequence of IGF II
![Page 17: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/17.jpg)
Sequences of insulin and IGFs compared
![Page 18: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/18.jpg)
Precursors of insulin and IGFs
proinsulin
proIGF I
proIGF II
![Page 19: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/19.jpg)
IGF II Insulin
3D structures of insulin and IGF
![Page 20: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/20.jpg)
The GH-IGF-Somatic axis
![Page 21: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/21.jpg)
Isaksson
![Page 22: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/22.jpg)
The GH-IGF-Somatic axis
![Page 23: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/23.jpg)
Endocrine control of mammary gland
![Page 24: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/24.jpg)
Mammary gland development
![Page 25: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/25.jpg)
Prolactin induces synthesis of the following proteins:
CaseinAlpha-lactalbuminLactose synthaseFatty acid synthetase
![Page 26: MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY LECTURE 7 - Mechanism of action of growth hormone and prolactin Growth hormone: general actions; receptor; signal.](https://reader036.fdocuments.us/reader036/viewer/2022062511/55160091550346cf6f8b5b37/html5/thumbnails/26.jpg)
Cytokine signalling
From: Shillingford et al (2001)