Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro

Serres, Murielle P.; Zlotek-Zlotkiewicz, Ewa; Concha, Carolina; Gurian-West, Mark; Daburon, Virginie; Roberts, James M.; Besson, Arnaud

doi:10.1038/onc.2011.9

Cited by 65 publications

(75 citation statements)

References 51 publications

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“…The expressed mutant protein has lost its cell cycle functions (Besson et al, 2006;Vlach et al, 1997) and its quantity in the cytoplasm is increased in resting cells compared to wild-type p27 kip1 (Serres et al, 2011). In addition, p27 kip1 CK 2 knock-in mice have increased overall expression levels of the mutant protein compared to the level of p27 kip1 observed in wild-type mice (Besson et al, 2006).…”

Section: Pser10-p27mentioning

confidence: 74%

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Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Gui

Labrousse

Goethem

et al. 2014

Journal of Cell Science

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Infiltration of macrophages into tissue can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid migrationcommon to all leukocytes, and mesenchymal migration -restricted to macrophages and certain tumour cells. Here, we investigate the initiating mechanisms involved in macrophage mesenchymal migration. We show that a single macrophage is able to use both migration modes. Macrophage mesenchymal migration is correlated with decreased activity of Rho/Rho-associated protein kinase (ROCK) and is potentiated when ROCK is inhibited, suggesting that amoeboid inhibition participates in mechanisms that initiate mesenchymal migration. We identify the cyclindependent kinase (CDK) inhibitor p27 kip1 (also known as CDKN1B)as a new effector of macrophage 3D-migration. By using p27 kip1 mutant mice and small interfering RNA targeting p27 kip1 , we show that p27 kip1 promotes mesenchymal migration and hinders amoeboid migration upstream of the Rho/ROCK pathway, a process associated with a relocation of the protein from the nucleus to the cytoplasm. Finally, we observe that cytoplasmic p27 kip1 is required for in vivo infiltration of macrophages within induced tumours in mice. This study provides the first evidence that silencing of amoeboid migration through inhibition of the Rho/ROCK pathway by p27 kip1 participates in the onset of macrophage mesenchymal migration.

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Section: Pser10-p27mentioning

confidence: 74%

“…Urethane is a potent carcinogen that induces lung tumours in mice that are frequently infiltrated with macrophages Serres et al, 2011). We used previously described lung tissues from urethane-treated p27 kip12/2 and p27 kip1 CK 2 mouse cohorts to carry out F4/80 labelling to stain macrophages (Serres et al, 2011).…”

Section: Pser10-p27mentioning

confidence: 99%

Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Gui

Labrousse

Goethem

et al. 2014

Journal of Cell Science

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“…Additionally, it also performs cyclin-CDK-independent functions in apoptosis, cytoskeleton rearrangement and transcriptional regulation (Baldassarre et al, 2005;Timmerbeul et al, 2006;Wu et al, 2006;le Sage et al, 2007;Larrea et al, 2009;Belletti et al, 2010;Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011). However, different and sometimes contradictory findings have been reported about the role of p27 in the regulation of cell migration (Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011).…”

Section: Results P27mentioning

confidence: 95%

“…However, the function of p27 in cell motility has not yet been fully elucidated (Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011). By employing genetically disrupted p27…”

Section: Discussionmentioning

confidence: 99%

“…However, a growing body of evidence shows that the retention of p27 in the cytoplasm leads to the protein adopting an oncogenic role in the regulation of cytoskeletal dynamics and cell migration (Besson et al, 2004a;Besson et al, 2008). The exact function of cytoplasmic p27 is thus an active focus of several recent studies, but different and sometimes contradictory findings have been reported (Liu et al, 2010;See et al, 2010;Bhatia et al, 2010;Borriello et al, 2011;Fearon, 2011;Serres et al, 2011;Wander et al, 2011). In our current studies, we used time-lapse microscopy to monitor the random migration of p27 +/+ and p27 2/2 mouse embryonic fibroblasts (MEFs) in real time.…”

Section: Introductionmentioning

confidence: 99%

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Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

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Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 has been reported, but the exact mechanism(s) whereby p27 intersects with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27+/+ MEFs with genetically ablated p27−/− MEFs using wound healing, transwell and time-lapse microscopic analyses, we provide direct evidence demonstrating that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression which was further mediated by ERKs/ATF1-dependent transactivation of CRE within the stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucially negative role in cell migration by inhibiting MnSOD expression in a STAT-3 dependent manner.

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Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1

Zhou

Lei

Chen

et al. 2023

Clinical & Translational Med

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Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

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Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro

Cited by 65 publications

References 51 publications

Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1

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