| First Author | Rygiel TP | Year | 2008 |
| Journal | J Cell Sci | Volume | 121 |
| Issue | Pt 8 | Pages | 1183-92 |
| PubMed ID | 18349077 | Mgi Jnum | J:139599 |
| Mgi Id | MGI:3808952 | Doi | 10.1242/jcs.017194 |
| Citation | Rygiel TP, et al. (2008) The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation. J Cell Sci 121(Pt 8):1183-92 |
| abstractText | Tiam1 is a ubiquitously expressed activator of the small GTPase Rac. Previously, we found that Tiam1 knockout (KO) mice are resistant to DMBA-induced skin tumorigenicity, which correlated with increased apoptosis in keratinocytes of the skin epidermis. Here, we have studied the mechanisms by which Tiam1 protects against apoptosis. We found that Tiam1-KO keratinocytes show increased apoptosis in response to apoptotic stimuli, including growth factor deprivation and heat-shock treatment. Expression of catalytically active Tiam1, but not inactive Tiam1, rescues the apoptosis susceptibility of Tiam1-KO keratinocytes, indicating that this defect is caused by impaired Tiam1-mediated Rac activation. Apoptosis induced by growth factor starvation correlates with impaired ERK phosphorylation in Tiam1-KO keratinocytes. Moreover, Tiam1-KO keratinocytes contain lower levels of intracellular reactive oxygen species (ROS) when compared with wild-type cells. The ROS content of keratinocytes is dependent on both Tiam1 and the activity of NADPH oxidase (Nox), and is required for ERK-mediated survival signaling. Indeed, Tiam1 deficiency or the inhibition of intracellular ROS production blocks ERK phosphorylation and sensitizes wild-type keratinocytes to apoptotic stimuli. Our results indicate that the Rac activator Tiam1 controls the intracellular redox balance by Nox-mediated ROS production, which regulates ERK phosphorylation and the susceptibility of keratinocytes to apoptotic signaling. |
