MK3 Modulation Affects BMI1-Dependent and Independent Cell Cycle Check-Points
Publication Date
April 08, 2015
Journal
PLOS ONE
Authors
Peggy Prickaerts, Hanneke E. C. Niessen, Vivian E. H. Dahlmans, Frank Spaapen, et al
Volume
10
Issue
4
Pages
e0118840
DOI
https://dx.plos.org/10.1371/journal.pone.0118840
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0118840
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/25853770
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390245
Europe PMC
http://europepmc.org/abstract/MED/25853770
Scopus
84929483883
Mendeley
http://www.mendeley.com/research/mk3-modulation-affects-bmi1dependent-independent-cell-cycle-checkpoints
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Mendeley | Further Information

{"title"=>"MK3 modulation affects BMI1-dependent and independent cell cycle check-points", "type"=>"journal", "authors"=>[{"first_name"=>"Peggy", "last_name"=>"Prickaerts", "scopus_author_id"=>"55491514500"}, {"first_name"=>"Hanneke E.C.", "last_name"=>"Niessen", "scopus_author_id"=>"7004569904"}, {"first_name"=>"Vivian E.H.", "last_name"=>"Dahlmans", "scopus_author_id"=>"57200294781"}, {"first_name"=>"Frank", "last_name"=>"Spaapen", "scopus_author_id"=>"15758772300"}, {"first_name"=>"Juliette", "last_name"=>"Salvaing", "scopus_author_id"=>"6507470207"}, {"first_name"=>"Jolien", "last_name"=>"Vanhove", "scopus_author_id"=>"55235188700"}, {"first_name"=>"Claudia", "last_name"=>"Geijselaers", "scopus_author_id"=>"55491461900"}, {"first_name"=>"Stefanie J.J.", "last_name"=>"Bartels", "scopus_author_id"=>"24449257200"}, {"first_name"=>"Iris", "last_name"=>"Partouns", "scopus_author_id"=>"56648170300"}, {"first_name"=>"Dietbert", "last_name"=>"Neumann", "scopus_author_id"=>"7202067341"}, {"first_name"=>"Ernst Jan", "last_name"=>"Speel", "scopus_author_id"=>"7003812124"}, {"first_name"=>"Yoshihiro", "last_name"=>"Takihara", "scopus_author_id"=>"7004840121"}, {"first_name"=>"Bradly G.", "last_name"=>"Wouters", "scopus_author_id"=>"7006091000"}, {"first_name"=>"Jan Willem", "last_name"=>"Voncken", "scopus_author_id"=>"7004387295"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84929483883", "doi"=>"10.1371/journal.pone.0118840", "scopus"=>"2-s2.0-84929483883", "pui"=>"604108653", "issn"=>"19326203"}, "id"=>"677efc4f-2d49-3f61-8d94-88426750f121", "abstract"=>"Copyright: © 2015 Prickaerts et al. Although the MK3 gene was originally found deleted in some cancers, it is highly expressed in others. The relevance ofMK3 for oncogenesis is currently not clear. We recently reported that MK3 controls ERK activity via a negative feedbackmechanism. This prompted us to investigate a potential role for MK3 in cell proliferation. We here show that overexpression of MK3 induces a proliferative arrest in normal diploid human fibroblasts, characterized by enhanced expression of replication stress- and senescence-associated markers. Surprisingly, MK3 depletion evokes similar senescence characteristics in the fibroblastmodel.We previously identifiedMK3 as a binding partner of Polycomb Repressive Complex 1 (PRC1) proteins. In the current study we show thatMK3 overexpression results in reduced cellular EZH2 levels and concomitant loss of epigenetic H3K27me3-marking and PRC1/chromatin-occupation at the CDKN2A/INK4A locus. In agreement with this, the PRC1 oncoprotein BMI1, but not the PCR2 protein EZH2, bypasses MK3-induced senescence in fibroblasts and suppresses P16 < sup > INK4A < /sup > expression. In contrast, BMI1 does not rescue the MK3 loss-of-function phenotype, suggesting the involvement of multiple different checkpoints in gain and loss of MK3 function. Notably, MK3 ablation enhances proliferation in two different cancer cells. Finally, the fibroblastmodel was used to evaluate the effect of potential tumorigenic MK3 drivermutations on cell proliferation and M/SAPK signaling imbalance. Taken together, our findings support a role for MK3 in control of proliferation and replicative life-span, in part through concerted action with BMI1, and suggest that the effect of MK3 modulation or mutation onM/ SAPK signaling and, ultimately, proliferation, is cell context-dependent.", "link"=>"http://www.mendeley.com/research/mk3-modulation-affects-bmi1dependent-independent-cell-cycle-checkpoints", "reader_count"=>4, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Ph. D. Student"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Ph. D. Student"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>2}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2010293"], "description"=>"<p>(A) Proliferation curves (left) of U-2OS cells expressing a retroviral <i>MK3</i> vector (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>; filled circles) or an empty vector (con; open circles); overexpression of GST-MK3 (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>) in U-2OS cells detected with and GST or a MK3-antiserum (right panel). Cell counts at t = 2 through t = 8 were normalized to cell counts at t = 0 for each transduced cell culture individually (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#sec013\" target=\"_blank\">Methods</a> section for details); statistical significance was determined by two-tailed Student’s t-test and is presented relative to the empty vector control (* p < 0.05). (B) Phase contrast images showing cell morphology in U-2OS/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells and control cells. (C) Protein expression levels of the check-point regulator proteins TP53 and p21<sup>CIP1/WAF1</sup> (P21) in U-2OS/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells; loading control b-Actin (bAct). (D) DNA profile analysis of U-2OS/<i>MK3OE</i> versus control cells (4–6 days post-transduction; representative experiment). <i>MK3</i><sup><i>WT</i></sup>overexpression elicits an intra S-phase arrest: table shows a substantially increased S-phase occupancy. (E) Immunohistochemical staining for phosphorylated H2A.X (γH2A.X) and phosphorylated KAP1pSer824 (pKAP1; arrows) to visualize DNA damage in U-2OS/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cultures; control (top panels) or <i>MK3</i><sup><i>WT</i></sup><i>OE</i> (bottom panels).</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371593, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g005", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proliferative_regulation_by_MK3_in_cancer_cell_lines_/1371593", "title"=>"Proliferative regulation by MK3 in cancer cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010291"], "description"=>"<p>(A) Expression levels of the PRC proteins EZH2, CBX8 and PHC1 in senescing TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells at ±3–4 weeks post-transduction; loading control b-Actin (bAct). (B) Expression levels of the PRC proteins EZH2, CBX8 and PHC1 in senescing TIG3/<i>shMK3</i> cells at ±2–3 weeks post-transduction; loading control b-Actin (bAct). (C) Chromatin immunoprecipitation (ChIP) analysis of MK3, H3K27me3, CBX8, PHC1 enrichment in <i>MK3</i><sup><i>WT</i></sup><i>OE</i> (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>) expressing and control (<i>con</i>) TIG3 cells; PRC1-target loci (p<i>16 promoter</i>, <i>p16exon1</i>, <i>HOXA10</i>, <i>HOXA11)</i> and non-target loci (p15exon1, p14exon1) are indicated below the figure. Enrichments are presented as percentages of total input. Negative control HA antiserum. Experiments were performed three times; results of one representative experiment are shown (statistical significance: * p<0.05, ** p<0.01; t-test).</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371591, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_links_between_MK3_and_PRC_in_proliferative_life_span_/1371591", "title"=>"Functional links between MK3 and PRC in proliferative life span.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010292"], "description"=>"<p>TIG3 cells were sequentially transduced with either <i>Bmi1</i>.<i>ires</i>.<i>GFP</i> (<i>Bmi1OE</i>) or <i>GFP</i> (con) virus, and <i>MK3</i>/<i>puromycin</i> (<i>MK3OE</i>) or control <i>puromycin</i> virus (con) at 48 hrs intervals. Retroviral vectors expressing murine <i>Bmi1/</i>GFP reporter were transduced first (or empty vector control), followed by a MK3/<i>puromycin</i> resistance marker (or empty vector control). Transduction of <i>Bmi1OE</i> and control transduced cells was simultaneously carried out with the same <i>MK3</i><sup><i>WT</i></sup><i>OE</i> viral preparation (or control virus) to minimize inter-experimental variation. Cells were grown on selection medium and proliferation capacity was tested ± 2–3 weeks post-transduction. (A) Proliferation curves of normal human TIG3 fibroblasts transduced with a retroviral <i>MK3</i><sup><i>WT</i></sup><i>overexpression</i> vector (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>; black symbols) or <i>shcon</i> vector (white symbols), in conjunction with either an empty vector control (con; circles) or a murine <i>Bmi1</i> expression vector (<i>Bmi1OE</i>; triangles). (B) Proliferation curves of normal human TIG3 fibroblasts transduced with a retroviral <i>MK3</i> knock-down vector (<i>shMK3</i>; black symbols) or <i>shcon</i> vector (white symbols), in conjunction with either an empty vector control (con; circles) or a murine <i>Bmi1</i> expression vector (<i>Bmi1OE</i>; squares). Cell counts at t = 2 through t = 8 (A, B) were normalized to cell counts at t = 0 for each transduced cell culture individually (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#sec013\" target=\"_blank\">Methods</a> section for details); statistical significance was determined by two-tailed Student’s t-test and is presented relative to the empty vector control (* p < 0.05). (C) Comparative morphology of TIG3 cells expression <i>Bmi1</i> and/or <i>MK3</i> versus control cells as recorded by GFP fluorescent imaging ± 3 weeks after transduction (D) Immunoblot analysis of EZH2, CBX4, RNF2 and H3K27me3 in <i>MK3</i><sup><i>WT</i></sup><i>OE</i>, <i>Bmi1OE</i>, <i>Bmi1OE/MK3</i><sup><i>WT</i></sup><i>OE</i> and <i>control</i> TIG3 cell lysates. (E) Expression analysis of BMI1, MK3, and TP53 at the indicated time points in (corresponding to experiment in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#pone.0118840.g004\" target=\"_blank\">Fig 4C</a>). Cells were grown on selection medium and analysed at 1 or 4 weeks after serial transduction; expression vectors and antibodies are indicated in the figure. Early and late samples were loaded on the same gel for BMI1 analysis; corresponding sections are shown separately.</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371592, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g004", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_links_between_MK3_and_PRC_in_proliferative_life_span_/1371592", "title"=>"Functional links between MK3 and PRC in proliferative life span.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010290"], "description"=>"<p>(A) Cell morphology in TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells (phase contrast; right upper panel); senescence-associated beta-Galactosidase (SA-bGal) staining in TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells (right lower panel). (B) Protein expression levels of MK3, TP53, P21<sup>CIP1/WAF1</sup> (P21) and P16<sup>INK4A</sup> (P16) in TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>) <i>versus</i> control (<i>con</i>) cell lysates; loading control: b-Actin (bAct). TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells were cultured for approximately 3–4 weeks prior to extraction. (C) Nuclear TP53 accumulation in senescent TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells; counterstaining: DAPI. (D) Phase contrast images showing cello morphology in TIG3/<i>shMK3</i> cells (<i>shMK3</i>, lower panel; phase contrast) <i>versus</i> control cells (<i>shcon;</i> upper panel). Retrovirally transduced TIG3 cells (<i>shcon</i> and <i>shMK3</i>) were submitted to puromycin selection for 3–4 days, and plated at equal density (20–25% confluency) at the onset of the experiment; pictures were taken when <i>shcon</i> cells reached confluency. (E) Analysis of protein expression in TIG3/<i>shMK3</i> and control (<i>shcon</i>) cell lysates: TP53, P21<sup>CIP1/WAF1</sup> (P21) and P16<sup>INK4A</sup> (P16); loading control: b-Actin (bAct).</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371590, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g002", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_MK3_WT_OE_induced_proliferative_block_in_normal_cells_correlates_with_induction_of_known_senescence_markers_/1371590", "title"=>"The <i>MK3</i><sup><i>WT</i></sup><i>OE</i>-induced proliferative block in normal cells correlates with induction of known senescence markers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010295", "https://ndownloader.figshare.com/files/2010296", "https://ndownloader.figshare.com/files/2010297", "https://ndownloader.figshare.com/files/2010298", "https://ndownloader.figshare.com/files/2010299", "https://ndownloader.figshare.com/files/2010300", "https://ndownloader.figshare.com/files/2010301", "https://ndownloader.figshare.com/files/2010302", "https://ndownloader.figshare.com/files/2010303", "https://ndownloader.figshare.com/files/2010304"], "description"=>"<div><p>Although the MK3 gene was originally found deleted in some cancers, it is highly expressed in others. The relevance of MK3 for oncogenesis is currently not clear. We recently reported that MK3 controls ERK activity via a negative feedback mechanism. This prompted us to investigate a potential role for MK3 in cell proliferation. We here show that overexpression of MK3 induces a proliferative arrest in normal diploid human fibroblasts, characterized by enhanced expression of replication stress- and senescence-associated markers. Surprisingly, MK3 depletion evokes similar senescence characteristics in the fibroblast model. We previously identified MK3 as a binding partner of Polycomb Repressive Complex 1 (PRC1) proteins. In the current study we show that MK3 overexpression results in reduced cellular EZH2 levels and concomitant loss of epigenetic H3K27me3-marking and PRC1/chromatin-occupation at the <i>CDKN2A/INK4A</i> locus. In agreement with this, the PRC1 oncoprotein BMI1, but not the PCR2 protein EZH2, bypasses MK3-induced senescence in fibroblasts and suppresses P16<sup>INK4A</sup> expression. In contrast, BMI1 does not rescue the MK3 loss-of-function phenotype, suggesting the involvement of multiple different checkpoints in gain and loss of MK3 function. Notably, MK3 ablation enhances proliferation in two different cancer cells. Finally, the fibroblast model was used to evaluate the effect of potential tumorigenic MK3 driver-mutations on cell proliferation and M/SAPK signaling imbalance. Taken together, our findings support a role for MK3 in control of proliferation and replicative life-span, in part through concerted action with BMI1, and suggest that the effect of MK3 modulation or mutation on M/SAPK signaling and, ultimately, proliferation, is cell context-dependent.</p></div>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371595, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0118840.s001", "https://dx.doi.org/10.1371/journal.pone.0118840.s002", "https://dx.doi.org/10.1371/journal.pone.0118840.s003", "https://dx.doi.org/10.1371/journal.pone.0118840.s004", "https://dx.doi.org/10.1371/journal.pone.0118840.s005", "https://dx.doi.org/10.1371/journal.pone.0118840.s006", "https://dx.doi.org/10.1371/journal.pone.0118840.s007", "https://dx.doi.org/10.1371/journal.pone.0118840.s008", "https://dx.doi.org/10.1371/journal.pone.0118840.s009", "https://dx.doi.org/10.1371/journal.pone.0118840.s010"], "stats"=>{"downloads"=>6, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MK3_Modulation_Affects_BMI1_Dependent_and_Independent_Cell_Cycle_Check_Points_/1371595", "title"=>"MK3 Modulation Affects BMI1-Dependent and Independent Cell Cycle Check-Points", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010294"], "description"=>"<p>(A) Proliferation profiles of U-2OS/<i>shMK3</i> cells (left panel; filled squares)) and HeLa/<i>shMK3</i> cells (right panel; filled squares) <i>versus</i> control (<i>shcon</i>; open circles). (B) Proliferation profiles of TIG3 cells expressing MK3 mutants MK3P28S (<i>MK3</i><sup><i>P28S</i></sup><i>OE</i>; filled triangles) or MK3E105A (<i>MK3</i><sup><i>E105A</i></sup><i>OE</i>; open triangles) at 1 week post-transduction (left panel) and 4 weeks post-transduction (right panel). The dotted lines in the graphs represent the MK3WT proliferation profiles, as depicted in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#pone.0118840.s002\" target=\"_blank\">S2A Fig</a>. Cell counts at t = 2 through t = 8 (A, B) were normalized to cell counts at t = 0 for each transduced cell culture individually (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#sec013\" target=\"_blank\">Methods</a> section for details); statistical significance was determined by two-tailed Student’s t-test and is presented relative to the empty vector control (* p < 0.05). (C) Protein expression profiles of GST-tagged MK3 (GST:MK3), endogenous MK3 (MK3<sup>endo</sup>), ERK, phosphorylated ERK (pERK) P38, TP53 and p16<sup>INK4A</sup> (P16) in TIG3 cells at indicated timepoints post-transduction (corresponding to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#pone.0118840.g004\" target=\"_blank\">Fig 4B</a>); loading controls: b-Actin (bAct).</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371594, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modulation_of_MK3_levels_leads_to_M_SAPK_signalling_imbalance_/1371594", "title"=>"Modulation of MK3-levels leads to M/SAPK signalling imbalance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2010289"], "description"=>"<p>(A) Retroviral expression systems were applied to enhance (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>) or remove (<i>shMK3</i>) MK3 expression. Western blot shows MK3 proteins: endogenous (MK3<sup>endo</sup>) and overexpressed (GST:MK3). (B) Proliferation curves of TIG3 cells transduced with: a retroviral <i>MK3</i> expression vector (<i>MK3</i><sup><i>WT</i></sup><i>OE</i>; filled circles), an empty vector (con; open circles) or a murine <i>Bmi1</i> expression vector (open triangles); proliferation was determined at 1 week (top panel) or ±4 weeks (bottom panel) after retroviral transduction of TIG3 cells. Cell counts at t = 2 through t = 8 were normalized to cell counts at t = 0 for each transduced cell culture individually (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118840#sec013\" target=\"_blank\">Methods</a> section for details); statistical significance was determined by two-tailed Student’s t-test and is presented relative to the empty vector control (* p < 0.05). (C) Quantification of DNA profiles (BrdU pulse-labeling and S-phase quantification by FACS) in TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells at approximately 1 week post-transduction. <i>RasV12</i>-transduced cells were used as a positive control. (D) <i>MK3</i><sup><i>WT</i></sup><i>OE</i> reduces <i>de novo</i> DNA synthesis in TIG3/<i>MK3</i><sup><i>WT</i></sup><i>OE</i> cells; cell counts: control (con) 699 BrdU-positive cells/10 fields; <i>MK3</i><sup><i>WT</i></sup><i>OE</i>: 442 BrdU-positive cells/9 fields.</p>", "links"=>[], "tags"=>["MK 3 ablation", "prc", "p 16INK expression", "fibroblast model", "pcr", "3k", "EZH 2 levels", "MK 3", "MK 3 function", "bmi", "Polycomb Repressive Complex 1", "Cell proliferation", "MK 3 depletion", "MK 3 modulation", "MK 3 gene", "CDKN 2A locus", "MK 3 overexpression results", "MK 3 controls ERK activity"], "article_id"=>1371589, "categories"=>["Uncategorised"], "users"=>["Peggy Prickaerts", "Hanneke E. C. Niessen", "Vivian E. H. Dahlmans", "Frank Spaapen", "Juliette Salvaing", "Jolien Vanhove", "Claudia Geijselaers", "Stefanie J. J. Bartels", "Iris Partouns", "Dietbert Neumann", "Ernst-Jan Speel", "Yoshihiro Takihara", "Bradly G. Wouters", "Jan Willem Voncken"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118840.g001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MK3_WT_overexpression_induces_a_proliferative_arrest_in_normal_human_fibroblasts_/1371589", "title"=>"<i>MK3</i><sup><i>WT</i></sup> overexpression induces a proliferative arrest in normal human fibroblasts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-08 03:21:43"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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