p14^Arf 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.

Permanent activation of HMGA2 in lipomas mimics its temporal physiological activation linked to the gain of adipose tissue

“…To test this hypothesis, we have stimulated adipose tissue explants by FGF1, a key regulator of mammalian adipogenesis known to activate HMGA2 in the murine immortalized preadipocyte cell line 3T3-L1 (18) as well as in human ADSC (19). Stimulation of explants of human adipose tissue from four donors for 24 h resulted in a highly significant upregulation of HMGA2 (Figure 1).…”

“…In MSC, as well as in uterine leiomyomas, the increase of HMGA2 was found to be accompanied by an increased expression of p14 Arf (19).…”

HMGA2 expression in white adipose tissue linking cellular senescence with diabetes

“…Arf (Markowski et al 2011a). Due to the fact that MSCs are part of WAT, we analyzed the distribution of p14…”

“…Arf (Markowski et al 2011a), an upstream agonist of p53 driving apoptosis and senescence. Since the main players within that network are well-conserved among mammals, these latter effects can be considered being part of an ancient mechanism preventing activated mesenchymal stem cells from undergoing malignant transformation.…”

“…Arf , p53, and CDKN1A and subsequently an increase in senescent cells (Markowski et al 2011a). Generally, an increase in senescent cells is believed to contribute to age-related diseases.…”