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PubMed | University of Udine, Italian National Cancer Institute and European Institute of Oncology at the IFOM IEO Campus
Type: Journal Article | Journal: Journal of molecular cell biology | Year: 2016

Exposure of normal and tumor-derived cells to TGF results in different outcomes, depending on the regulation of key targets. The CDK inhibitor p27(Kip1) is one of these TGF targets and is essential for the TGF-induced cell cycle arrest. TGF treatment inhibits p27(Kip1) degradation and induces its nuclear translocation, through mechanisms that are still unknown. Recent evidences suggest that SUMOylation, a post-translational modification able to modulate the stability and subcellular localization of target proteins, critically modifies members of the TGF signaling pathway. Here, we demonstrate that p27(Kip1) is SUMOylated in response to TGF treatment. Using different p27(Kip1) point mutants, we identified lysine 134 (K134) as the residue modified by small ubiquitin-like modifier 1 (SUMO1) in response to TGF treatment. TGF-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27(Kip1). We observed that SUMOylation regulated p27(Kip1) binding to CDK2, thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187. Importantly, p27(Kip1) SUMOylation was necessary for proper cell cycle exit following TGF treatment. These data indicate that SUMOylation is a novel regulatory mechanism that modulates p27(Kip1) function in response to TGF stimulation. Given the involvement of TGF signaling in cancer cell proliferation and invasion, our data may shed light on an important aspect of this pathway during tumor progression.


Citro S.,European Institute of Oncology at the IFOM IEO Campus
Frontiers in bioscience (Scholar edition) | Year: 2013

Although sharing a common conjugation pathway, SUMO1, SUMO2/3 and SUMO4 seem to play preferential roles in the cell. Recently, many regulatory mechanisms contributing to SUMO paralogs specific modification have emerged. SUMO enzymes can discriminate between SUMO paralogs at both conjugation and deconjugation levels. Moreover, many substrates possess characteristics that promote their preference for different SUMO family members. A better knowledge of the mechanisms promoting SUMO specific modification will improve our understanding of the functions of SUMO paralogs in distinct cellular pathways.


Campaner S.,European Institute of Oncology at the IFOM IEO Campus | Spreafico F.,European Institute of Oncology at the IFOM IEO Campus | Burgold T.,European Institute of Oncology at the IFOM IEO Campus | Doni M.,European Institute of Oncology at the IFOM IEO Campus | And 4 more authors.
Molecular Cell | Year: 2011

p53 is the central regulator of cell fate following genotoxic stress and oncogene activation. Its activity is controlled by several posttranslational modifications. Originally defined as a critical layer of p53 regulation in human cell lines, p53 lysine methylation by Set7/9 (also called Setd7) was proposed to fulfill a similar function in vivo in the mouse, promoting p53 acetylation, stabilization, and activation upon DNA damage (Kurash et al., 2008). We tested the physiological relevance of this circuit in an independent Set7/9 knockout mouse strain. Deletion of Set7/9 had no effect on p53-dependent cell-cycle arrest or apoptosis following sublethal or lethal DNA damage induced by radiation or genotoxic agents. Set7/9 was also dispensable for p53 acetylation following irradiation. c- myc oncogene-induced apoptosis was also independent of Set7/9, and analysis of p53 target genes showed that Set7/9 is not required for the p53-dependent gene expression program. Our data indicate that Set7/9 is dispensable for p53 function in the mouse. © 2011 Elsevier Inc.


PubMed | European Institute of Oncology at the IFOM IEO Campus
Type: Journal Article | Journal: EMBO molecular medicine | Year: 2010

It is generally accepted that a distinguishing property of stem cells (SCs), as compared to their more differentiated progenitors, is that of infrequent division, often referred to as quiescence. As regards hematopoietic stem cells (HSC), their resistance to antiproliferative drugs supports this notion. Maintenance of quiescence is thought to be critical for the preservation of HSCs function.


PubMed | European Institute of Oncology at the IFOM IEO Campus
Type: Journal Article | Journal: Molecular cell | Year: 2011

p53 is the central regulator of cell fate following genotoxic stress and oncogene activation. Its activity is controlled by several posttranslational modifications. Originally defined as a critical layer of p53 regulation in human cell lines, p53 lysine methylation by Set7/9 (also called Setd7) was proposed to fulfill a similar function invivo in the mouse, promoting p53 acetylation, stabilization, and activation upon DNA damage (Kurash etal., 2008). We tested the physiological relevance of this circuit in an independent Set7/9 knockout mouse strain. Deletion of Set7/9 had no effect on p53-dependent cell-cycle arrest or apoptosis following sublethal or lethal DNA damage induced by radiation or genotoxic agents. Set7/9 was also dispensable for p53 acetylation following irradiation. c-myc oncogene-induced apoptosis was also independent of Set7/9, and analysis of p53 target genes showed that Set7/9 is not required for the p53-dependent gene expression program. Our data indicate that Set7/9 is dispensable for p53 function in the mouse.

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