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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, has been recently shown to activate the c-Jun NH2-terminal kinase 1 (JNK1) and induce caspase-3-mediated apoptosis in Hepa1c1c7 cells. However, the molecules of the signaling pathway that control the mitogen-activated protein kinase cascades induced by B(a)P and the interaction between those and apoptosis by B(a)P have not been well defined. We report here that B(a)P promoted Cdc42/Rac1, p21-activated kinase 1 (PAK1), and JNK1 activities in 293T and HeLa 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) facilitated B(a)P-induced activation of Cdc42/Rac1, PAK1, and JNK1, overexpression of mutated alpha PIX (L383R, L384S), which lacks guanine nucleotide exchange factor activity, SH3 domain-deleted alpha PIX (Delta  SH3), which lacks the ability to bind PAK, kinase-negative PAK1 (K299R), and kinase-negative SEK1 (K220A, K224L) inhibited B(a)P-triggered JNK1 activation. Interestingly, overexpression of alpha PIX (Delta  CH) and a catalytically active mutant PAK1 (T423E) accelerated B(a)P-induced apoptosis in HeLa cells, whereas alpha PIX (Delta  SH3), PAK1 (K299R), and SEK 1 (K220A, K224L) inhibited B(a)P-initiated apoptosis. Finally, a preferential caspase inhibitor, Z-Asp-CH2-DCB, strongly blocked the alpha PIX (Delta  CH)-enhanced apoptosis in cells treated with B(a)P but did not block PAK1/JNK1 activation. Taken together, these results indicate that alpha PIX plays a crucial role in B(a)P-induced apoptosis through activation of the JNK1 pathway kinases.

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

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.


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