PubMed Journals: J Bone Miner Res

  Source:		PMID: 12162494

    		J Bone Miner Res. 2002 Aug;17(8):1401-7.
			Induction of transcriptional activity of
			the cyclic adenosine monophosphate response
			element binding protein by parathyroid hormone
			and epidermal growth factor in osteoblastic

			Swarthout JT(1), Tyson DR, Jefcoat SC Jr,
			Partridge NC.

			Author Information
			(1) Department of Pharmacological and Physiological
			Science, Saint Louis University School of
			Medicine, Missouri, USA.

			Erratum in J Bone Miner Res. 2002 Oct;17(10):1917.
			Efcoat, Stephen CJ Jr [corrected to Jefcoat,
			Stephen CJ Jr].

			Previously, we have shown that parathyroid
			hormone (PTH) transactivation of cyclic
			adenosine monophosphate (cAMP) response
			element binding protein (CREB) requires
			both serine 129 (S129) and serine 133 (S133)
			in rat osteosarcoma cells UMR 106-01 (UMR)
			cells. Furthermore, although protein kinase
			A (PKA) is responsible for phosphorylation
			at S133, glycogen synthase kinase 3beta
			(GSK-3beta) activity is required and may
			be responsible for phosphorylation of CREB
			at S129. Here, we show, using the GAL4-CREB
			reporter system, that epidermal growth factor
			(EGF) can transactivate CREB in UMR cells
			in addition to PTH. Additionally, treatment
			of UMR cells with both PTH and EGF results
			in greater than additive transactivation
			of CREB. Furthermore, using mutational analysis
			we show that S129 and S133 are required
			for EGF-induced transcriptional activity.
			EGF activates members of the MAPK family
			including p38 and extracellular signal-activated
			kinases (ERKs), and treatment of UMR cells
			with either the p38 inhibitor (SB203580)
			or the MEK inhibitor (PD98059) prevents
			phosphorylation of CREB at S133 by EGF but
			not by PTH. Treatment of cells with either
			SB203580 or PD98059 alone or together significantly
			inhibits transactivation of CREB by EGF
			but not by PTH, indicating that EGF regulates
			CREB phosphorylation and transactivation
			through p38 and ERKs and PTH does not. Finally,
			the greater than additive transactivation
			of CREB by PTH and EGF is significantly
			inhibited by the PKA inhibitor H-89 or by
			cotreatment with SB203580 and PD98059. Thus,
			several different signaling pathways in
			osteoblastic cells can converge on and regulate
			CREB activity. This suggests, in vivo, that
			circulating agents such as PTH and EGF are
			acting in concert to exert their effects.

			DOI: 10.1359/jbmr.2002.17.8.1401 PMID: 12162494
			[Indexed for MEDLINE]

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