Transforming Growth Factor-β1 Increases Bad Phosphorylation and Protects Neurons Against Damage

Abstract

Despite the characterization of neuroprotection by transforming growth factor-beta1 (TGF-beta1), the signaling pathway mediating its protective effect is unclear. Bad is a proapoptotic member of the Bcl-2 family and is inactivated on phosphorylation via mitogen-activated protein kinase (MAPK). This study attempted to address whether MAPK signaling and Bad phosphorylation were influenced by TGF-beta1 and, furthermore, whether these two events were involved in the antiapoptotic effect of TGF-beta1. We found a gradual activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and MAPK-activated protein kinase-1 (also called Rsk1) and a concomitant increase in Bad phosphorylation at Ser(112) in mouse brains after adenovirus-mediated TGF-beta1 transduction under nonischemic and ischemic conditions induced by transient middle cerebral artery occlusion. Consistent with these effects, the ischemia-induced increase in Bad protein level and caspase-3 activation were suppressed in TGF-beta1-transduced brain. Consequently, DNA fragmentation, ischemic lesions, and neurological deficiency were significantly reduced. In cultured rat hippocampal cells, TGF-beta1 inhibited the increase in Bad expression caused by staurosporine. TGF-beta1 concentration- and time-dependently activated Erk1/2 and Rsk1 accompanied by an increase in Bad phosphorylation. These effects were blocked by U0126, a mitogen-activated protein kinase/Erk kinase 1/2 inhibitor, suggesting an association between Bad phosphorylation and MAPK activation. Notably, U0126 and a Rsk1 inhibitor (Ro318220) abolished the neuroprotective activity of TGF-beta1 in staurosporine-induced apoptosis, indicating that activation of MAPK is necessary for the antiapoptotic effect of TGF-beta1 in cultured hippocampal cells. Together, we demonstrate that TGF-beta1 suppresses Bad expression under lesion conditions, increases Bad phosphorylation, and activates the MAPK/Erk pathway, which may contribute to its neuroprotective activity.

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

“…Unexpectedly, activated TGF-b attenuated HUVEC apoptosis. Although this observation is in line with several reports on the protective effect of TGF-b against apoptosis of cells other than HUVECs, 40,[49][50][51][52][53] our observations are not in complete accordance with the findings on the apoptosis-inducing effect of recombinant TGFb1 on bovine capillary endothelial cells. 5 While attempting to reproduce those findings, we observed that HUVECs were markedly resistant to TGF-b1-induced apoptosis (results not shown), consistent with observations by others.…”

Transforming Growth Factor Beta in the Central Nervous System

“…TGF-β1 administered into the brain reduced the infarct size dose dependently in experimental models of ischemia including permanent occlusion of the left middle cerebral artery by microbipolar electrocoagulation in mice (Prehn et al, 1993), autologous clot embolus injection into the right internal carotid artery in rabbit (Gross et al, 1993), and transient middle cerebral artery occlusion in rat (Zhu et al, 2002). In turn, antagonizing the endogenous action of TGF-β1 with a soluble TGF-β type II receptor resulted in a dramatic increase in infarct area (Ruocco et al, 1999).…”

Distinct Mechanisms for Neurotrophin-3-Induced Acute and Long-Term Synaptic Potentiation

“…Treatment with another PI3K inhibitor, wortmannin (100 nM) (Powis et al, 1994), also prevented the NT-3-induced increase in SSC frequency (data not shown). In contrast, inhibition of MAP kinase pathway by either 2Ј-amino-3Ј-methoxyflavone (PD098059) (10 M) (Alessi et al, 1995) or 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126) (10 M) (Zhu et al, 2002) did not abolish the NT-3-induced increase in SSC frequency (U0126, 5.3 Ϯ 0.6 events/min; PD098059, 5.2 Ϯ 7.8 events/min; U0126 with NT-3, 13.1 Ϯ 1.6 events/min; PD098059 with NT-3, 14.6 Ϯ 1.0) (Fig. 5A).…”