Antitumorigenic Effects of ZAK beta, an Alternative Splicing Isoform of ZAK

作者：Lee Jin Sun; Lin Yuh Yih; Wang Tsu Shing; Liu Jer Yuh; Lin Wei Wen; Yang Jaw Ji^*

来源：Chinese Journal of Physiology, 2018, 61(1): 25-34.

DOI：10.4077/CJP.2018.BAG528

• alternative splicing
• beta-catenin
• CREB1
• NF kappa B
• ZAK alpha
• ZAK beta

Sterile alpha motif (SAM)- and leucine-zipper-containing kinase (ZAK) plays a role in the regulation of cell cycle progression and oncogenic transformation. The ZAK gene generates two transcript variants, ZAK alpha and ZAK beta, through alternative splicing. In this study, we identified that ZAK alpha proteins were upregulated in tumor tissues, whereas ZAK beta proteins were mostly expressed in corresponding normal tissues. The ectopically expressed ZAK beta proteins in cancer cells inhibited cancer cell proliferation as well as anchorage-independent growth. The ZAK ss: ZAK alpha protein ratio played a role in the regulation of the cyclic adenosine monophosphate (cAMP) signaling pathway, whereas high ZAK beta protein levels led to the activation of cAMP response element binding protein 1 (CREB1) and exerted antitumor properties. Overexpression of ZAK beta or CREB1 cDNAs in cancer cells inhibited anchorage-independent growth and also reduced the levels of cyclooxygenase 2 (Cox2) and beta-catenin proteins. Cancer cells treated with doxorubicin (Doxo) resulted in the switching from the expression of ZAK alpha to ZAK beta and also inhibited cancer cell growth in soft agar, demonstrating that pharmacological drugs could be used to manipulate endogenous reprogramming splicing events and resulting in the activation of endogenous antitumorigenic properties. We showed that the two ZAK transcript variants, ZAK alpha and ZAK beta, had opposite biological functions in the regulation of tumor cell proliferation in that ZAK beta had powerful antitumor properties and that ZAK alpha could promote tumor growth.

• 出版日期2018-2-28
• 单位中国医科大学