Involvement of Alpha-PAK-Interacting Exchange Factor in the PAK1-c-Jun NH2-Terminal Kinase 1 Activation and Apoptosis Induced by Benzo[a]pyrene

doi:10.1128/MCB.21.20.6796-6807.2001

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Molecular and Cellular Biology, October 2001, p. 6796-6807, Vol. 21, No. 20
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.20.6796-6807.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Involvement of Alpha-PAK-Interacting Exchange Factor in the PAK1-c-Jun NH₂-Terminal Kinase 1 Activation and Apoptosis Induced by Benzo[a]pyrene

Shigeto Yoshii,¹^,² Masamitsu Tanaka,¹ Yoshiro Otsuki,¹ Toshiharu Fujiyama,¹ Hideki Kataoka,² Hajime Arai,² Hiroyuki Hanai,³ and Haruhiko Sugimura¹^,^*

First Department of Pathology,¹ First Department of Medicine,² and Department of Endoscopic & Photodynamic Medicine,³ Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan

Received 14 June 2001/Accepted 17 July 2001

Benzo[a]pyrene [B(a)P], a potent procarcinogen found in combustion products such as diesel exhaust and cigarette smoke, hasbeen recently shown to activate the c-Jun NH₂-terminal kinase1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7cells. However, the molecules of the signaling pathway that controlthe mitogen-activated protein kinase cascades induced by B(a)Pand the interaction between those and apoptosis by B(a)P havenot been well defined. We report here that B(a)P promoted Cdc42/Rac1,p21-activated kinase 1 (PAK1), and JNK1 activities in 293T andHeLa cells. Moreover, alpha-PAK-interacting exchange factor ( $alpha$ PIX) mRNA and its protein expression were upregulated by B(a)P.While overexpression of an active mutant of $alpha$ PIX ( $Delta$ CH) facilitatedB(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpressionof mutated $alpha$ PIX (L383R, L384S), which lacks guanine nucleotideexchange factor activity, SH3 domain-deleted $alpha$ PIX ( $Delta$ SH3), whichlacks the ability to bind PAK, kinase-negative PAK1 (K299R), andkinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggeredJNK1 activation. Interestingly, overexpression of $alpha$ PIX ( $Delta$ CH)and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-inducedapoptosis in HeLa cells, whereas $alpha$ PIX ( $Delta$ SH3), PAK1 (K299R), andSEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally,a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blockedthe $alpha$ PIX ( $Delta$ CH)-enhanced apoptosis in cells treated with B(a)Pbut did not block PAK1/JNK1 activation. Taken together, theseresults indicate that $alpha$ PIX plays a crucial role in B(a)P-inducedapoptosis through activation of the JNK1 pathwaykinases.

^* Corresponding author. Mailing address: First MCB 92-01 Department of Pathology, Hamamatsu University School of Medicine, 3600Handa-cho, Hamamatsu 431-3192, Japan. Phone: 81-53-435-2220. Fax:81-53-435-2225. E-mail: hsugimur{at}hama-med.ac.jp.

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