title: The c-Jun N-terminal kinase JNK functions upstream of Aurora B to promote entry into mitosis.
abstract: Mitogen-activated protein kinases (MAPKs) are components of signaling cascades regulated by environmental stimuli. In addition to participating in the stress response, the MAPKs c-Jun N-terminal Kinases JNK1 and JNK2 regulate the proliferation of normal and neoplastic cells. JNKs contribute to these processes largely by phosphorylating c-Jun and thus contributing to the activation of the AP-1 complex. We here report that JNKs control entry into mitosis. We have observed that JNK activity and phosphorylation of c-Jun become elevated during the G2/M transition of the cell cycle in immortalized fibroblasts and ovarian granulosa cells. Pharmacological inhibition of JNK causes a profound cell cycle arrest at the G2/M transition in both cell types. This effect is specific as it occurs with two distinct small molecule compounds. Inactivation of JNK prior to mitosis prevents expression of Aurora B and phosphorylation of Histone-H3 at Ser 10. Silencing of JNK1 and 2 causes a similar effect, whereas overexpression of JNK1 and 2 causes the opposite effect. Inhibition of JNK delays activation of cdc-2 and prevents downregulation of Cyclin B1. We conclude that JNK signaling promotes entry into mitosis by promoting expression of Aurora B and thereby phosphorylation of Histone-H3.
authors.affiliation: New York Medical College, Valhalla, NY 10595, USA. kutluk.oktay@kutlukoktay.com
authors.forename: Kutluk
authors.initials: K
authors.lastname: Oktay
authors.forename: Erkan
authors.initials: E
authors.lastname: Buyuk
authors.forename: Ozgur
authors.initials: O
authors.lastname: Oktem
authors.forename: Maja
authors.initials: M
authors.lastname: Oktay
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001973:Bromodeoxyuridine; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006107:Granulosa Cells; D006657:Histones / Q000378:metabolism; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D006657:Histones; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine