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dc.contributor.authorZaidi, Sayyed K.
dc.contributor.authorPande, Sandhya
dc.contributor.authorPratap, Jitesh
dc.contributor.authorGaur, Tripti
dc.contributor.authorGrigoriu, Simina R.
dc.contributor.authorAli, Syed A.
dc.contributor.authorStein, Janet L.
dc.contributor.authorLian, Jane B.
dc.contributor.authorVan Wijnen, Andre J.
dc.contributor.authorStein, Gary S.
dc.date2022-08-11T08:08:57.000
dc.date.accessioned2022-08-23T16:13:41Z
dc.date.available2022-08-23T16:13:41Z
dc.date.issued2007-12-14
dc.date.submitted2008-09-08
dc.identifier.citationProc Natl Acad Sci U S A. 2007 Dec 11;104(50):19861-6. Epub 2007 Dec 5. <a href="http://dx.doi.org/10.1073/pnas.0709650104">Link to article on publisher's site</a>
dc.identifier.issn1091-6490 (Electronic)
dc.identifier.doi10.1073/pnas.0709650104
dc.identifier.pmid18077419
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33684
dc.description.abstractThe osteogenic Runt-related (Runx2) transcription factor negatively regulates proliferation and ribosomal gene expression in normal diploid osteoblasts, but is up-regulated in metastatic breast and prostate cancer cells. Thus, Runx2 may function as a tumor suppressor or an oncogene depending on the cellular context. Here we show that Runx2-deficient primary osteoblasts fail to undergo senescence as indicated by the absence of beta-gal activity and p16(INK4a) tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p21(WAF1/CIP1) and p19(ARF) expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21(WAF/CIP1) and p19(ARF) mRNA and protein resulting in cell-cycle inhibition. Accumulation of spontaneous phospho-H2A.X foci, loss of telomere integrity and the Mre11/Rad50/Nbs1 DNA repair complex, and a delayed DNA repair response all indicate that Runx2 deficiency leads to genomic instability. We propose that Runx2 functions as a tumor suppressor in primary diploid osteoblasts and that subnuclear targeting contributes to Runx2-mediated tumor suppression.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18077419&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148388/pdf/zpq19861.pdf
dc.subjectAnimals; Cell Aging; Cell Nucleus; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Core Binding Factor Alpha 1; Subunit; Cyclin-Dependent Kinase Inhibitor p21; Gene Targeting; Genomic Instability; Mice; Mice, Knockout; Osteoblasts
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleRunx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume104
dc.source.issue50
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/349
dc.identifier.contextkey622934
html.description.abstract<p>The osteogenic Runt-related (Runx2) transcription factor negatively regulates proliferation and ribosomal gene expression in normal diploid osteoblasts, but is up-regulated in metastatic breast and prostate cancer cells. Thus, Runx2 may function as a tumor suppressor or an oncogene depending on the cellular context. Here we show that Runx2-deficient primary osteoblasts fail to undergo senescence as indicated by the absence of beta-gal activity and p16(INK4a) tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p21(WAF1/CIP1) and p19(ARF) expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21(WAF/CIP1) and p19(ARF) mRNA and protein resulting in cell-cycle inhibition. Accumulation of spontaneous phospho-H2A.X foci, loss of telomere integrity and the Mre11/Rad50/Nbs1 DNA repair complex, and a delayed DNA repair response all indicate that Runx2 deficiency leads to genomic instability. We propose that Runx2 functions as a tumor suppressor in primary diploid osteoblasts and that subnuclear targeting contributes to Runx2-mediated tumor suppression.</p>
dc.identifier.submissionpathgsbs_sp/349
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages19861-6
dc.contributor.studentSandhya Pande


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