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  • CDK S phosphorylation status influences the differential


    CDK5-S47 phosphorylation status influences the differential cellular proliferation versus migration response: Previous work from our laboratory has shown CDK5 to be a critical determinant of the cellular proliferation-migration dichotomy whereby CDK5 activation downstream of stimulated epidermal growth factor receptor triggers cell migration and decreases cell proliferation [16]. Our present work further adds to the repertoire of mechanisms that a cell may employ to differentially regulate a pro-mitotic vs pro-migratory response by controlling the phosphorylation status of S47 on CDK5. The formation of the CDK5-p35 complex has been shown to be required to suppress neuronal SC 144 regardless of CDK5 activity [25]. Based on our current work, phosphorylation of S47 also achieves the same phenotype i.e. relieves the cell cycle suppression by disrupting the CDK5-p35 interaction (Fig. 4). Taken together with the inhibition of cell migration in cells expressing the S47D CDK5 mutant (Fig. 3), reversible phosphorylation of S47 on CDK5 presents a quick, physiologically relevant mechanism to help cells conform to the proliferation-migration dichotomy.
    Acknowledgements We thank Dr. Pradipta Ghosh (UCSD) and Dr. Michael Ford (MS Bioworks) for their help with the structural and mass spectrometry analyses, respectively. We thank Dr. Vasanthy Narayanaswami (CSULB) for critically reading the manuscript and Reyalyn Villegas (CSULB) for technical assistance. This work was supported by the National Institute of General Medical Sciences (NIGMS) award numbers UL1GM118979, TL4GM118980, RL5GM118978; and the CSULB Office of Research and Sponsored programs grant. DB is supported by the NIGMS grant #SC2GM121246. JN and KBO are supported by the NIGMS awards #T34GM008074 and #R25GM071638, respectively. The content of the manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
    Introduction Chemotherapy is considered as the standard treatment for advanced or recurrent cervical and colon cancer [1,2]. However, resistance to chemotherapy occurs, thus substantially compromising the efficacy of chemotherapy to treat advanced or recurrent cancer. The molecular mechanisms leading to chemoresistance are complex and involve activity changes of membrane transporters to reduce intracellular drug concentration; alterations in drug-target interaction; increased cell ability to repair drug-induced DAN damage and defects of apoptotic pathways [3]. Identification of drugs that can overcome chemoresistance is important to improve the clinical management of cancer patients. Cyclin-dependent kinases (CDK) are critically required for the regulation and expression of the large number of components necessary for the passage through the eukaryotic cell cycle [4]. Apart from cell cycle, CDK family members play important roles in gene transcription, metabolism, neuronal differentiation and development [5]. Deregulated hyperactivity of CDK due to overexpression or mutation has been reported in several human cancers [6]. Constitutive active CDKs leads to aberrant tumor cell proliferation through phosphorylating and modulating the activity of proteins involved in cell cycle. AT7519 is a multitargeted CDK inhibitor that selectively inhibits CDK1, 2, 4, 5 and 9 [7]. AT7519 has been evaluated in preclinical models and are currently in clinical trial for the treatment of a variety of cancers including lymphoma, multiple myeloma and chronic lymphoblastic leukemia [4,[8], [9], [10], [11], [12], [13]]. In this study, we systematically investigated the anti-cancer activity of AT7519 focusing on its in vitro as well as in vivo effects on chemoresistant cervical and colon cancer cells. Using multiple cell lines and xenograft mouse models, we demonstrate that AT7519 is a promising candidate to overcome chemoresistance in cervical and colon cancer. The molecular mechanisms of AT7519's action in chemo-resistant cancer cells are likely to be the inhibition of CDK and RNA transcription.