FOXM1 regulates proliferation, senescence and oxidative stress in keratinocytes and cancer cells

Smirnov, Artem; Panatta, Emanuele; Lena, AnnaMaria; Castiglia, Daniele; Daniele, Nicola Di; Melino, Gerry; Candi, Eleonora

doi:10.18632/aging.100988

Cited by 53 publications

(35 citation statements)

References 44 publications

(59 reference statements)

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“…Foxm1 that encodes a transcription factor with key roles in maintaining the balance between proliferation and differentiation was also upregulated in middle-aged MR EKO versus CO skin (two-fold; Figure 3a). It has been reported that Foxm1 contributes to the high proliferative potential of keratinocytes and that its decrease in aging can induce keratinocyte apoptosis and senescence (Smirnov et al, 2016).…”

Section: Middle-aged Mr Epidermal Knockout Skin Features Compartment-mentioning

confidence: 99%

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

Bigas

Sevilla

Pérez

2020

Journal of Investigative Dermatology

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The increased production of endogenous glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacologic treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We reported that epidermal MR plays nonredundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. A 13-month-old MR epidermal knockout (MR EKO ) mice showed differential features of aging relative to controls (CO) in all skin compartments. MR EKO mice were resistant to age-induced epidermal atrophy but showed reduced dermal thickness, with decreased collagen deposition and decreased SMAD2 and 3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MR EKO versus CO, featuring adipocyte hyperplasia and hypertrophy at least in part through early increases in Pparg. These changes correlated with compartment-specific alterations in GC signaling. In addition, conditioned medium from MR EKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of b-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and bcatenin signaling pathways.

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Section: Middle-aged Mr Epidermal Knockout Skin Features Compartment-mentioning

confidence: 99%

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

Bigas

Sevilla

Pérez

2020

Journal of Investigative Dermatology

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“…FOXM1 depletion sensitizes normal keratinocytes to apoptosis and ROS-induced apoptosis. This characterizes FOXM1 as a key regulator of ROS in dividing normal epithelial cells 20 .…”

Section: ■ Discussionmentioning

confidence: 99%

The role of vitamin C in the gene expression of oxidative stress markers in fibroblasts from burn patients

et al. 2018

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“…This appears to be the case of FoxM1. Not only FoxM1 repression translates into mild aneuploidy levels, but also FoxM1 might further act by counteracting age-associated cellular damage caused by genotoxic and oxidative stresses 42,60 .…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of mitotic decline during human aging

Macedo

Vaz

Bakker

et al. 2018

Preprint

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Aneuploidy, an abnormal chromosome number, has been linked to aging and age-20 associated diseases, but the underlying molecular mechanisms remain unknown. Supported by 21 direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, 22 we found that aneuploidy increases with aging due to general dysfunction of the mitotic Aging has been linked to an increase in aneuploidy for the past several decades 1 . This 34 association has been well documented for oocytes and is considered to be the main cause of 35 miscarriage and birth defects in humans 2 . However, aneuploidy can also arise in somatic cells, 36 and a number of studies have reported age-dependent increases in aneuploidy [3][4][5][6][7] . These studies 37 have shown that aging is positively correlated with the incidence of chromosome mis- The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; and the lower mitotic indexes of elderly cell cultures has limited these studies from clearly 43 demonstrating whether mitotic genes are repressed intrinsically in old dividing cells. Moreover, 44 analysis of the mitotic process in aging models and diseases has been scarce and a 45 comprehensive analysis of cell division efficiency in naturally aged cells is largely missing. 46More recently, aneuploidy has been also linked to aging. Studies of aneuploidy-prone mouse 47 models exhibiting increased rates of chromosome mis-segregation uncovered a unanticipated 48 nexus with the rate of aging and the development of age-related pathologies [11][12][13][14] Results 72Aneuploidy increases during natural aging 73In our study we used human dermal fibroblasts (HDFs) collected from healthy Caucasian males 74 with ages ranging from neonatal to octogenarian ( Supplementary Fig.1a), to test whether The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/261008 doi: bioRxiv preprint first posted online Feb. 6, 2018; strict quantitative parameters by microscopy analysis, in the proliferating fibroblast cultures from 89 older individuals and the HGPS patient ( Supplementary Fig.1b-g), thus validating their 90 suitability as models of advanced and premature aging, respectively. 91To determine if aneuploidy increases with aging, we performed fluorescence in situ 92 hybridization (FISH) analysis for three chromosome pairs. We found significantly higher 93 aneusomy indexes in asynchronous cell populations of middle-aged, old-aged and progeria 94 samples (Fig. 1a,b). However, because aneuploid cells are most likely outcompeted in culture by 95 diploid cells 17 , thereby diluting the aneuploidy index, we additionally measured aneuploidy in a 96 post-mitotic cell subpopulation generated during a 24h treatment with the cytokinesis inhibitor 97 cytochalasin D (Fig. 1a,c). Using this approach, we observed even higher aneuploidy in the 98 middle-aged, old-aged and progeria cultures. Thus, the mild aneuploidy levels found ...

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FOXM1 regulates proliferation, senescence and oxidative stress in keratinocytes and cancer cells

Cited by 53 publications

References 44 publications

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

The role of vitamin C in the gene expression of oxidative stress markers in fibroblasts from burn patients

Molecular basis of mitotic decline during human aging

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