The ability of cells to arrest proliferation and to enter a G1-arrested or G0 (quiescent) state is critical for tumor suppression. Retinoblastoma (RB) family proteins, including p130, mediate G0/G1 arrest in mammalian cells by mechanisms that are not fully understood. Upon entry into G0/G1, p130 is recruited into the DNA-binding DREAM protein complex (DP, RB-like, E2F, and MuvB core). The MuvB core of 5 proteins (LIN9, LIN37, LIN52, LIN54, and RBBP4) plays a dual role in transcriptional control. When bound to p130 in G0/G1, the MuvB core forms the DREAM complex and represses more than 800 cell cycle-dependent genes. When released from DREAM, the MuvB core binds to BMYB to activate mitotic genes. DYRK1A protein kinase plays a critical role in promoting assembly of the DREAM complex by phosphorylating the LIN52 subunit, which is required for binding between the p130 and MuvB core. Inhibition of DYRK1A is sufficient to block assembly of the DREAM complex and to override G0/G1 arrest. The DYRK1A gene is mapped to a Down syndrome (DS) critical region, and its upregulation due to trisomy 21 contributes to mental impairment in people with DS. It is important to establish the role of DYRK1A in tumor suppression because of its potential value as a therapeutic target to improve the cognitive functions of people with DS. Previous studies have revealed an essential role of DYRK1A in G0/G1 arrest, mediated by RB family, as well as in oncogenic Ras-induced senescence. Furthermore, biochemical data suggest that DYRK1A is downstream of LATS2 kinase in the Hippo tumor suppressor pathway. Our preliminary analysis found that the DYRK1A gene undergoes frequent copy number loss in high-grade ovarian carcinoma, suggesting that inactivation of DYRK1A contributes to the pathogenesis of ovarian cancer. We hypothesize that inactivation of DYRK1A in ovarian cancer due to genetic losses or aberrant regulation (such as loss of LATS-mediated activation) could promote ovarian carcinogenesis by disrupting the assembly and function of the DREAM complex. We propose to test this hypothesis by characterizing DYRK1A pathways in cells using the following strategy.
In Aim 1, we will determine whether loss of DYRK1A contributes to the malignant transformation of the ovarian cancer precursor cells and whether gain of DYRK1A function can suppress the growth of ovarian cancers in vitro and in vivo.
In Aim 2, we will determine the role of the Hippo pathway in regulating DYRK1A and the DREAM complex. Since the function and regulation of DYRK1A in cells is not fully understood, we identified DYRK1A-interacting proteins.
In Aim 3, we will characterize novel DYRK1A-interacting proteins that have been prioritized by their potential significance in development and cancer, and establish the role of these factors in the growth arrest functions of DYRK1A. The proposed biochemical and functional characterization of DYRK1A-regulated pathways will advance our knowledge of quiescence, improve our understanding of the pathogenesis of ovarian cancer, and establish whether DYRK1A can be safely targeted to treat DS.
Cell proliferation is controlled by the mechanisms that promote quiescence and senescence; deregulation of these processes leads to cancer. DYRK1A protein kinase is required for quiescence and senescence by promoting the functions of the retinoblastoma family of tumor suppressors. The mechanisms of function and regulation of DYRK1A are poorly understood, therefore we propose to elucidate the DYRK1A signaling pathway, which controls cell proliferation and could play a role in the pathogenesis of cancer.
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| Iness, Audra N; Felthousen, Jessica; Ananthapadmanabhan, Varsha et al. (2018) The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb. Oncogene : |
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| Odajima, Junko; Saini, Siddharth; Jung, Piotr et al. (2016) Proteomic Landscape of Tissue-Specific Cyclin E Functions in Vivo. PLoS Genet 12:e1006429 |
