English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Tools annual

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Presents the access of premium content as premium feature

Premium Content

Global: Zendy Plus annual

Global: Zendy Free Plan

Background  Four and a half LIM-only protein 2 (FHL2) has been implicated in multiple signaling pathways that regulate cell growth and tissue homeostasis. We reported previously that FHL2 regulates cyclin D1 expression and that immortalized  FHL2 -null mouse embryo fibroblasts (MEFs) display reduced levels of cyclin D1 and low proliferative activity.    Methodology/Principal Findings  Here we address the contribution of FHL2 in cell transformation by investigating the effects of oncogenic Ras in  FHL2 -null context. We show that H-RasV12 provokes cell cycle arrest accompanied by accumulation of p53 and p16 INK4a  in immortalized  FHL2 −/−   MEFs. These features contrast sharply with Ras transforming activity in wild type cell lines. We further show that establishment of  FHL2 -null cell lines differs from conventional immortalization scheme by retaining functional p19 ARF /p53 checkpoint that is required for cell cycle arrest imposed by Ras. However, after serial passages of Ras-expressing  FHL2 −/−   cells, dramatic increase in the levels of D-type cyclins and Rb phosphorylation correlates with the onset of cell proliferation and transformation without disrupting the p19 ARF /p53 pathway. Interestingly, primary  FHL2 -null cells overexpressing cyclin D1 undergo a classical immortalization process leading to loss of the p19 ARF /p53 checkpoint and susceptibility to Ras transformation.    Conclusions/Significance  Our findings uncover a novel aspect of cellular responses to mitogenic stimulation and illustrate a critical role of FHL2 in the signalling network that implicates Ras, cyclin D1 and p53.

The LIM-Only Protein FHL2 Mediates Ras-Induced Transformation through Cyclin D1 and p53 Pathways