Cell Cycle Disruption in Wild Rodent Populations as an Endpoint in Detecting Exposure and Effect

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.

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Diversity of murine norovirus in wild-rodent populations: species-specific associations suggest an ancient divergence

Journal of General Virology ◽

10.1099/vir.0.036392-0 ◽

2012 ◽

Vol 93 (2) ◽

pp. 259-266 ◽

Cited By ~ 29

Author(s):

Donald B. Smith ◽

Nora McFadden ◽

Richard J. Blundell ◽

Anna Meredith ◽

Peter Simmonds

Keyword(s):

Wild Mouse ◽

Murine Norovirus ◽

Laboratory Mice ◽

Wild Rodent ◽

Reading Frame ◽

Wood Mice ◽

Wild House Mice ◽

Species Specific ◽

Rodent Populations ◽

Murine Noroviruses

A survey of wild-rodent populations has revealed that murine norovirus (MNV) is present and diverse in wild-house mice Mus musculus. This virus is genetically similar to MNV infecting show mice and previously described variants circulating in laboratory mice. The detection of MNV in wild-mouse populations suggests that MNV infection of laboratory mice and show mice (from which laboratory mice are derived) derives from contact with or their origins from wild-mouse progenitors. The survey additionally identified frequent infection of wood mice (Apodemus sylvaticus) with genetically divergent variants of MNV. These viruses are distinct from previously described MNV variants, differing by 22–23 % over the complete genome sequence compared with a maximum of 13 % between M. musculus-derived strains. Comparison with other noroviruses reveals that the Apodemus MNV groups with MNV in genogroup V and shares the same overall genome organization, predicted lengths of proteins encoded by ORFs 1–3 and the existence of a conserved alternative reading frame in VP1 encoding a homologue of the MNV ORF4. Different Apodemus MNV isolates were as variable as MNV isolates and showed evidence for inter-isolate recombination. Our observation of species-specific associations of MNV variants in wild populations suggests that murine noroviruses have an ancient origin, a feature that they may share with other norovirus genogroups.

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Investigation and genome characterisation of tatenale hantavirus in wild rodent populations in the United Kingdom

Access Microbiology ◽

10.1099/acmi.ac2019.po0555 ◽

2019 ◽

Vol 1 (1A) ◽

Author(s):

Joseph G Chappell ◽

Theocharis Tsoleridis ◽

C. Patrick McClure ◽

Malcolm Bennett ◽

Rachael E Tarlinton ◽

...

Keyword(s):

United Kingdom ◽

Wild Rodent ◽

The United Kingdom ◽

Rodent Populations

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Nuclear failure, DNA damage, and cell cycle disruption after migration through small pores: a brief review

Essays in Biochemistry ◽

10.1042/ebc20190007 ◽

2019 ◽

Vol 63 (5) ◽

pp. 569-577

Author(s):

Charlotte R. Pfeifer ◽

Manasvita Vashisth ◽

Yuntao Xia ◽

Dennis E. Discher

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Local Density ◽

Nuclear Lamina ◽

Nuclear Deformation ◽

Nuclear Factors ◽

A Cell ◽

Dense Tissue ◽

Cell Cycle Disruption ◽

Dependent Processes

Abstract In many contexts of development, regeneration, or disease such as cancer, a cell squeezes through a dense tissue or a basement membrane, constricting its nucleus. Here, we describe how the severity of nuclear deformation depends on a nucleus’ mechanical properties that are mostly determined by the density of chromatin and by the nuclear lamina. We explain how constriction-induced nuclear deformation affects nuclear contents by causing (i) local density changes in chromatin and (ii) rupture of the nuclear lamina and envelope. Both processes mislocalize diffusible nuclear factors including key DNA repair and regulatory proteins. Importantly, these effects of constricted migration are accompanied by excess DNA damage, marked by phosphorylated histone γH2AX in fixed cells. Rupture has a number of downstream consequences that include a delayed cell cycle—consistent with a damage checkpoint—and modulation of differentiation, both of which are expected to affect migration-dependent processes ranging from wound healing to tumorigenic invasion.

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