title: p14Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells-implications for benign tumorigenesis.
abstract: HMGA2 is a major regulator of benign tumorigenesis from mesenchyme-derived tissues and stem-cell self-renewal. It has been postulated that HMGA2 mediates its critical function by decreasing p16(Ink4a)/p14(Arf) expression and cellular senescence. To repress the oncogenic activity of HMGA2, the lin-28-let-7 axis is thought to increasingly repress the expression of HMGA2 with age. To understand the HMGA2-p14(Arf) -relationship in benign tumorigenesis, we performed a series of experiments on mesenchymal stem-cells, i.e., the proposed cells of origin of lipomas and uterine leiomyomas. The expression of both genes was inversely correlated during senescence in vitro but contrary to the expectations in adipose tissue derived stem cells (ADSCs) stimulation of HMGA2 by FGF1 increased the expression of p14(Arf) . Based on the assumption that in ADSCs p14(Arf) is repressing HMGA2, siRNA silencing of p14(Arf) was performed resulting in a significant upregulation of HMGA2. To see if p14(Arf) can repress HMGA2 by a TP53-dependent mechanism, nutlin-3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta-galactosidase, but also decreased the expression of HMGA2, suggesting that p14(Arf) indeed influences HMGA2 by a p53-dependent mechanism because nutlin-3 stabilizes p53. Accordingly, the HMGA2 response triggered by serum was reduced by treatment of ADSCs with nutlin-3. As to the interaction between HMGA2 and p14(Arf) in benign tumorigenesis, we propose a model where akin to MSC self-renewal during tissue repair the simultaneous increase of p14(Arf) with HMGA2 ensures genomic stability, whereas in turn p14(Arf) can repress HMGA2 via TP53.
authors: Center of Human Genetics, University of Bremen, Germany.
authors: Dominique Nadine
authors: DN
authors: Markowski
authors: Nina
authors: N
authors: Winter
authors: Frauke
authors: F
authors: Meyer
authors: Inga
authors: I
authors: von Ahsen
authors: Heiner
authors: H
authors: Wenk
authors: Ingo
authors: I
authors: Nolte
authors: Jörn
authors: J
authors: Bullerdiek
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic; D005809:Genes, Regulator; D025743:HMGA2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
chemical_list: D025743:HMGA2 Protein; D025803:Tumor Suppressor Protein p14ARF