Abstract 659: Overexpression of TPX2 accelerates cell cycle progression in melanoma and is an indicator of response to Aurora A kinase inhibitors

2010 ◽  
Author(s):  
Bin Li ◽  
M. Dalla Palma ◽  
K. L. Nathanson ◽  
G. Xu ◽  
K. Smalley ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Cycle Progression

scholarly journals Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6003
Author(s):  
Majd S. Hijjawi ◽  
Reem Fawaz Abutayeh ◽  
Mutasem O. Taha
Keyword(s):  
Anticancer Agents ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Resonance Energy ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Characteristic Analysis ◽  
Mesenchymal Transition ◽  
Intermolecular Contacts

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

scholarly journals Identification of Aurora-A as a Direct Target of E2F3 during G2/M Cell Cycle Progression

2008 ◽  
Vol 283 (45) ◽  
pp. 31012-31020 ◽  
Author(s):  
Lili He ◽  
Hua Yang ◽  
Yihong Ma ◽  
W. Jack Pledger ◽  
W. Douglas Cress ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Aurora A ◽  
M Cell ◽  
Cycle Progression ◽  
Direct Target

scholarly journals Cyclin F-Chk1 synthetic lethality mediated by E2F1 degradation

2019 ◽  
Author(s):  
Kamila Burdova ◽  
Hongbin Yang ◽  
Roberta Faedda ◽  
Samuel Hume ◽  
Daniel Ebner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Multiple Substrates ◽  
Cyclin F

SummaryCyclins are central engines of cell cycle progression when partnered with Cyclin Dependent Kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but forms an E3 ubiquitin ligase, assembling through the F-box domain, an Skp1-Cul1-F-box (SCF) module. Although multiple substrates of cyclin F have been identified the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging cells with more than 200 kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. The DNA replication catastrophe depends on the accumulation of E2F1 in cyclin F depleted cells. We observe that SCFcyclin F promotes E2F1 degradation after Chk1 inhibitors in a CDK dependent manner. Thus, Cyclin F restricts E2F1 activity during cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.

Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1199-1199
Author(s):  
Tomonari Takemura ◽  
Satoki Nakamura ◽  
Yasuyuki Nagata ◽  
Daisuke Yokota ◽  
Isao Hirano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cycle Progression ◽  
Abl Kinase ◽  
Abl Kinase Inhibitors

Abstract Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cortactin Modulates RhoA Activation and Expression of Cip/Kip Cyclin-Dependent Kinase Inhibitors To Promote Cell Cycle Progression in 11q13-Amplified Head and Neck Squamous Cell Carcinoma Cells

2010 ◽  
Vol 30 (21) ◽  
pp. 5057-5070 ◽  
Author(s):  
David R. Croucher ◽  
Danny Rickwood ◽  
Carole M. Tactacan ◽  
Elizabeth A. Musgrove ◽  
Roger J. Daly
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Fadu Cells ◽  
Phase Entry

ABSTRACT The cortactin oncoprotein is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC), often due to amplification of the encoding gene (CTTN). While cortactin overexpression enhances invasive potential, recent research indicates that it also promotes cell proliferation, but how cortactin regulates the cell cycle machinery is unclear. In this article we report that stable short hairpin RNA-mediated cortactin knockdown in the 11q13-amplified cell line FaDu led to increased expression of the Cip/Kip cyclin-dependent kinase inhibitors (CDKIs) p21WAF1/Cip1, p27Kip1, and p57Kip2 and inhibition of S-phase entry. These effects were associated with increased binding of p21WAF1/Cip1 and p27Kip1 to cyclin D1- and E1-containing complexes and decreased retinoblastoma protein phosphorylation. Cortactin regulated expression of p21WAF1/Cip1 and p27Kip1 at the transcriptional and posttranscriptional levels, respectively. The direct roles of p21WAF1/Cip1, p27Kip1, and p57Kip2 downstream of cortactin were confirmed by the transient knockdown of each CDKI by specific small interfering RNAs, which led to partial rescue of cell cycle progression. Interestingly, FaDu cells with reduced cortactin levels also exhibited a significant diminution in RhoA expression and activity, together with decreased expression of Skp2, a critical component of the SCF ubiquitin ligase that targets p27Kip1 and p57Kip2 for degradation. Transient knockdown of RhoA in FaDu cells decreased expression of Skp2, enhanced the level of Cip/Kip CDKIs, and attenuated S-phase entry. These findings identify a novel mechanism for regulation of proliferation in 11q13-amplified HNSCC cells, in which overexpressed cortactin acts via RhoA to decrease expression of Cip/Kip CDKIs, and highlight Skp2 as a downstream effector for RhoA in this process.

scholarly journals Ubiquitin signaling in cell cycle control and tumorigenesis

2020 ◽  
Author(s):  
Fabin Dang ◽  
Li Nie ◽  
Wenyi Wei
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Cell Cycle Control ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Cycle Progression ◽  
Precise Control ◽  
Cycle Regulation

Abstract Cell cycle progression is a tightly regulated process by which DNA replicates and cell reproduces. The major driving force underlying cell cycle progression is the sequential activation of cyclin-dependent kinases (CDKs), which is achieved in part by the ubiquitin-mediated proteolysis of their cyclin partners and kinase inhibitors (CKIs). In eukaryotic cells, two families of E3 ubiquitin ligases, anaphase-promoting complex/cyclosome and Skp1-Cul1-F-box protein complex, are responsible for ubiquitination and proteasomal degradation of many of these CDK regulators, ensuring cell cycle progresses in a timely and precisely regulated manner. In the past couple of decades, accumulating evidence have demonstrated that the dysregulated cell cycle transition caused by inefficient proteolytic control leads to uncontrolled cell proliferation and finally results in tumorigenesis. Based upon this notion, targeting the E3 ubiquitin ligases involved in cell cycle regulation is expected to provide novel therapeutic strategies for cancer treatment. Thus, a better understanding of the diversity and complexity of ubiquitin signaling in cell cycle regulation will shed new light on the precise control of the cell cycle progression and guide anticancer drug development.

scholarly journals Expression of Cyclin-Dependent Kinase Inhibitors in Epiphyseal Chondrocytes Induced to Terminally Differentiate with Thyroid Hormone

Endocrinology ◽  
2000 ◽  
Vol 141 (12) ◽  
pp. 4552-4557 ◽  
Author(s):  
R. Tracy Ballock ◽  
Xiaolan Zhou ◽  
Lynn M. Mink ◽  
Daniel H. C. Chen ◽  
Barry C. Mita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Hormone ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Terminal Differentiation ◽  
Cyclin Dependent Kinase ◽  
Growth Plate Chondrocytes ◽  
Cycle Progression ◽  
Cell Growth And Differentiation

Abstract A growing body of evidence suggests that systemic hormones and peptide growth factors may exert their effects on cell growth and differentiation in part through regulation of the cell division cycle. We hypothesized that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through controlling cell cycle progression at the G1/S restriction point. Our results support this hypothesis by demonstrating that treatment of epiphyseal chondrocytes with thyroid hormone under chemically defined conditions results in the arrest of DNA synthesis and the onset of terminal differentiation, indicating that thyroid hormone is one factor capable of regulating the transition between cell growth and differentiation in these cells. This terminal differentiation process is associated with induction of the cyclin/cyclin-dependent kinase inhibitors p21cip-1, waf-1 and p27kip1, suggesting that thyroid hormone may regulate terminal differentiation in part by arresting cell cycle progression through induction of cyclin-dependent kinase inhibitors.

scholarly journals The Drosophila F-box protein dSkp2 regulates cell proliferation by targeting Dacapo for degradation

2013 ◽  
Vol 24 (11) ◽  
pp. 1676-1687 ◽  
Author(s):  
Wen Dui ◽  
Bin Wei ◽  
Feng He ◽  
Wei Lu ◽  
Changqing Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Functional Relationship ◽  
Kinase Inhibitors ◽  
Cycle Progression ◽  
Cell Doubling Time ◽  
F Box Protein ◽  
Negative Factors

Cell cycle progression is controlled by a complex regulatory network consisting of interacting positive and negative factors. In humans, the positive regulator Skp2, an F-box protein, has been a subject of intense investigation in part because of its oncogenic activity. By contrast, the molecular and developmental functions of its Drosophila homologue, dSkp2, are poorly understood. Here we investigate the role of dSkp2 by focusing on its functional relationship with Dacapo (Dap), the Drosophila homologue of the cyclin-dependent kinase inhibitors p21cip1/p27kip1/p57kip2. We show that dSkp2 interacts physically with Dap and has a role in targeting Dap for ubiquitination and proteasome-mediated degradation. We present evidence that dSkp2 regulates cell cycle progression by antagonizing Dap in vivo. dSkp2 knockdown reduces cell density in the wing by prolonging the cell doubling time. In addition, the wing phenotype caused by dSkp2 knockdown resembles that caused by dap overexpression and can be partially suppressed by reducing the gene dose of dap. Our study thus documents a conserved functional relationship between dSkp2 and Dap in their control of cell cycle progression, suggesting the possibility of using Drosophila as a model system to study Skp2-mediated tumorigenesis.

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