The role of CDK5RAP2 in tumorigenesis and metastasis and its expression regulation

Abstract

Cyclin-dependent kinase-5, regulatory subunit-associated protein 2 (CDK5RAP2) plays a pivotal role in microtubule organization by interacting with γ-tubulin ring complex (γTuRC) to stimulate the nucleation of microtubules and also stabilizing microtubule plus ends by interacting with the +TIP end-binding protein 1 (EB1). The microtubule network is a major component of cytoskeleton and its important roles in multiple cellular functions, such as intracellular transport, cell division and cell migration, have been well documented. The aberrance of mitotic spindle localization and orientation leads to the shift of symmetric cell division to asymmetric cell division, which inhibits tumorigenesis by repressing the self-renew of cancer stem cells (CSCs). And the disorder of microtubules dynamics results in suppression of cell migration. In this study, we demonstrate that CDK5RAP2 expression is regulated by the canonical Wnt signaling pathway, in which the β-catenin-TCF/LEF complex is activated by interacting with histone modifying co-activator CREB-binding protein (CBP). And we identify that RNAi-mediated CDK5RAP2 depletion inhibited tumorigenesis by disrupting the orientation of mitotic spindles, which leads to the shift of CSCs division from symmetric division to asymmetric division. Moreover, knockout of CDK5RAP2 suppresses cancer metastasis by inhibiting cell migration through disturbing the formation of pseudopods. Taken together, CDK5RAP2 is indicated to be a promising therapy target for cancer treatment.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology