The goal of this project is to elucidate the function of cyclin C in tumorigenesis. In the proposed work we will focus on the role for cyclin C in T-cell lymphoblastic leukemia (T-ALL, in Aims 1 and 2), while in Aim 3 we will extend our analyses to prostate and lung cancers. Cyclin C was cloned over 20 years ago, together with cyclins D1 and E, in a screen for mammalian and Drosophila cDNAs that can complement mutations in Saccharomyces cerevisiae CLN1-3 genes. Subsequently, cyclins D1 and E have been extensively studied, and their involvement in cancer has been extremely well documented. In contrast, the role of cyclin C in human cancer is much less understood. In order to analyze the function of cyclin C in tumorigenesis, we generated conditional cyclin C knockout mice, using gene targeting in embryonic stem cells. Unexpectedly, we found that an acute ablation of cyclin C in hematopoietic cells led to a strong upregulation of intracellular Notch1 (ICN1) levels. We observed that cyclin C-CDK8 kinase phosphorylates ICN1, which in turn allows binding of ICN1 to an F-box protein Fbw7, and triggers ICN1 poly-ubiquitination and subsequent proteosomal degradation. Ablation of cyclin C disrupts this process, leading to strong upregulation of ICN1 levels. Analyses of conditional cyclin C knockout mice revealed that these animals display increased susceptibility to T-ALL. Importantly, cyclin C heterozygotes also display increased tumor susceptibility. Moreover, we observed that the cyclin C gene is heterozygously deleted in a substantial fraction of human T-ALL, and these tumors display reduced cyclin C levels. Collectively, these observations suggest that cyclin C likely functions in vivo as a haploinsufficient tumor-suppressor. In the proposed work we will extend these observations.
In Specific Aim 1, we will study the exact molecular function of cyclin C in T-ALL using human tumor cell lines.
In Specific Aim 2, we will utilize primary, patient-derived human T-ALL samples to search for mutations or deletions in genes encoding cyclin C kinase partners (cyclin-dependent kinases CDK8, CDK19 and CDK3).
In Aim 3, we will extend our studies to prostate and lung cancers.
The proposal focuses on a protein called cyclin C. Our preliminary results indicate that this protein may be involved in cancer formation. Understanding the function played by cyclin C in cancer may help to design rational cancer therapies.
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| Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95 |
| Hydbring, Per; Wang, Yinan; Bogorad, Roman L et al. (2017) Identification of cell cycle-targeting microRNAs through genome-wide screens. Cell Cycle 16:2241-2248 |
| Wang, Haizhen; Nicolay, Brandon N; Chick, Joel M et al. (2017) The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546:426-430 |
| Otto, Tobias; Candido, Sheyla V; Pilarz, Mary S et al. (2017) Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit. Proc Natl Acad Sci U S A 114:10660-10665 |
| Zhang, Qing-Hua; Yuen, Wai Shan; Adhikari, Deepak et al. (2017) Cyclin A2 modulates kinetochore-microtubule attachment in meiosis II. J Cell Biol 216:3133-3143 |
| Johannessen, Liv; Sundberg, Thomas B; O'Connell, Daniel J et al. (2017) Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. Nat Chem Biol 13:1102-1108 |
| Zhou, Jing; Tien, An-Chi; Alberta, John A et al. (2017) A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Rep 18:3167-3177 |
| Hydbring, Per; Wang, Yinan; Fassl, Anne et al. (2017) Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell 31:576-590.e8 |
| Liu, Lijun; Michowski, Wojciech; Inuzuka, Hiroyuki et al. (2017) G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat Cell Biol 19:177-188 |
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