Cdc42-dependent Mediation of UV-induced p38 Activation by G Protein βγ Subunits

Abstract

The beta and gamma subunits of heterotrimeric GTP-binding proteins (Gbetagamma) were found to bi-directionally regulate the UV-induced activation of p38 and c-Jun NH(2)-terminal kinase, and the UV-induced activation of p38 was reported to enhance the resistance of normal keratinocytes to apoptosis. However, the signaling pathway downstream of Gbetagamma for this UV-induced p38 activation is not known. Thus, we examined the role of the Rho GTPase family in the regulation of UV-induced p38 activation by Gbetagamma. We found that overexpression of Gbetagamma increased the UV-induced activation of Cdc42 and that overexpression of constitutively active V12 Cdc42 increased the UV-induced p38 activation. Transfection of dominant negative N17 Cdc42 or small interfering RNA for Cdc42 blocked UV-induced p38 activation mediated by Gbetagamma in COS-1 and HaCaT cells. UV-induced p38 activation by Gbetagamma was blocked by overexpression of dominant negative p21-activated kinase (PAK)-interacting exchange factor beta (betaPix), and wild type betaPix stimulated the UV-induced p38 activation, which was blocked by N17 Cdc42. Gbetagamma increased the UV-induced activation of Ras, and the overexpression of V12 Ras increased UV-induced p38 activation, which was blocked by dominant negative betaPix. UV-induced p38 activation was inhibited by N17 Ras and a farnesyltransferase inhibitor, manumycin A. Gbetagamma also increased the UV-induced phosphorylation of the epidermal growth factor receptor (EGFR), and the UV-induced p38 activation was blocked by an EGFR kinase inhibitor, AG1478. From these results, we conclude that Gbetagamma mediates UV-induced activation of p38 in a Cdc42-dependent way and that EGFR, Ras, and betaPix act sequentially upstream of Cdc42 in COS-1 and HaCaT cells.

Role and Interrelationship of Gα Protein, Hydrogen Peroxide, and Nitric Oxide in Ultraviolet B-Induced Stomatal Closure in Arabidopsis Leaves

“…In animal cells, it has been shown that UV-B activates the Ga-Gbg complex to release free Ga and Gbg, both of which result in HB-EGF secretion and subsequent activation of the EGF signal transduction pathway (Seo et al, 2004(Seo et al, , 2007Seo and Juhnn, 2010), suggesting that both Ga and Gbg are functional units to transmit UV-B signaling. However, until now, whether G proteins participate in the responses of plant cells to UV-B was not known.…”

“…However, few of the molecular players involved in UV-B signal transduction are currently known. In mammalian cells, heterotrimeric G proteins have been shown to mediate various UV-B-induced cellular responses, such as secretion of heparin-binding epidermal growth factor (HB-EGF), activation of mitogen-activated protein kinases, cyclooxygenase2 expression, and apoptosis in human keratinocytes (Seo et al, 2004(Seo et al, , 2007Seo and Juhnn, 2010), suggesting that G proteins are important molecular players in UV-B signal transduction. However, at present, whether G proteins participate in the responses of plant cells to UV-B is not known.…”

Genetic Background May Confer Susceptibility to PTC in Benign Multinodular Thyroid Disease

“…To this end, CDC42 that showed very high over-expression in HN + PTC compared to MNG merits further discussion. CDC42 is activated by some environmental factors such as gamma-radiation or UVB-light [13,14]. None of our patients had a documented history of medical or obvious environmental exposure to radiation.…”

Investigação de parceiros moleculares de Cdc42 em linhagens de células humanas submetidas a estresse genotóxico

“…Trabalhos recentes têm demonstrado também um possível papel na resposta ao dano no DNA. Foi observado que os níveis de Cdc42 ativada aumentam após o tratamento com UVC e Cdc42 é capaz de ativar p38 (Seo et al, 2004). Alguns trabalhos mostram que Cdc42 pode estar relacionado com o envelhecimento (Kerber et al, 2009;Wang et al, 2007;Florian et al, 2012) e que esta proteína pode promover a senescência de modo dependente de P53 (Wang et al, 2007).…”

“…Seo e colaboradores observaram que Cdc42 é ativado em células COS-1 tratadas com radiação UVC e foi observado também que Cdc42 promove a ativação de p38 induzida por UV (Seo et al, 2004) Analisando a porção C-terminal de Cdc42 foi identificado uma possível sequência sinal de localização nuclear (NLS) (Williams, 2003) e, recentemente, foi descoberta a translocação de Cdc42 para a membrana nuclear após o estresse de células fotorreceptoras por exposição excessiva à luz (Heynen et al, 2011).…”