Ligand structure influences autologous downregulation of estrogen receptor-alpha messenger RNA.

A series of A- and D-ring substituted estrogen analogues have been examined for their effect on estrogen receptor-alpha (ERalpha) mRNA downregulation. Recently it has been proposed that ERalpha autologous downregulation occurs via transcriptional repression exerted by the binding of the ERalpha-ligand complex to the 5' region of the coding region of the ERalpha gene. Placement of the phenolic hydroxyl group on the various carbons of the aromatic A-ring of estratrien-17betaol (carbons 1-3) produced ligands which diminished the steady state level of ERalpha mRNA in relation to their affinity for receptor.

Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation.

We have shown previously that GH stimulates the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal-regulated kinases) 1 and 2. To examine pathways coupling GH receptor (GHR) to MAP kinase activation, we have determined the effects of GH on SHC-growth factor receptor bound 2-son of Sevenless (SHC-Grb2-SOS) association and activation of Ras, Raf, and MAP-ERK kinase (MEK). GH promoted the rapid, transient association of SHC with the Grb2-SOS complex, which correlated with the time course of Ras, Raf, and MEK activation.

Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B.

GH is known to activate JAK2 tyrosine kinase and members of the Stat family of transcription factors, including Stats 1, 3, and 5. The recent observation that at least two Stat5 proteins (Stat5A and Stat5B) exist in mouse and human, raises the question of whether GH activates both Stat5A and Stat5B and, if so, whether the requirements for activation are the same. An initial report investigating this issue demonstrated GH-dependent activation of Stat5A but not Stat5B.

Cholecystokinin stimulates formation of shc-grb2 complex in rat pancreatic acinar cells through a protein kinase C-dependent mechanism.

Cholecystokinin (CCK) has recently been shown to activate the mitogen-activated protein kinase (MAPK) cascade (Ras-Raf-MAPK kinase-MAPK) in pancreatic acini. The mechanism by which the Gq protein-coupled CCK receptor activates Ras, however, is currently unknown. Growth factor receptors are known to activate Ras by means of adaptor proteins that bind to phosphotyrosine domains.

Signalling pathway of GH.

GH has long been known as a regulator of body growth and metabolism, yet its mechanism of action at the cellular level has been elusive. We have recently shown that GH promotes the rapid association of GH receptor with the tyrosine kinase JAK2, activates JAK2, and promotes the tyrosyl phosphorylation of both JAK2 and GH receptor. This suggests that the initial signalling event in GH action is the activation of JAK2 which in turn phosphorylates tyrosines within JAK2 and GH receptor.