Induction of Apoptosis-Like Mitochondrial Impairment Triggers Antioxidant and Bcl-2-Dependent Keratinocyte Differentiation

Tamiji, Susan; Beauvillain, Jean-Claudé; Mortier, Laurent; Jouy, Nathalie; Tual, Martine; Delaporte, E.; Formstecher, Pierre; Marchetti, Philippe; Polakowska, Renata

doi:10.1111/j.0022-202x.2005.23885.x

Cited by 33 publications

(29 citation statements)

References 56 publications

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“…Our data reveal increases in ROS production in both iASPP-silenced and differentiated keratinocytes. Previous studies have established that differentiationrelated changes, including induction of a flattened morphology, stratification and keratin-10 expression, were a consequence of ROS production (Tamiji et al, 2005). Our findings identify that UV-B exposure promotes the appearance of differentiation markers in keratinocytes.…”

Section: Discussionsupporting

confidence: 64%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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BSTRACTThe protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fissionfusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses.

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Section: Discussionsupporting

confidence: 64%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…The signaling pathways associated with this phenomenon are incompletely understood. However, mitochondrial oxidative stress was shown to promote epidermal differentiation in mice (40) and in culture (41), as did uncoupled mitochondria (42). Our studies of constitutive Sod2-deficient mice also showed increased keratinocyte differentiation (19), but early lethality complicated interpretation of this result.…”

Section: Discussionmentioning

confidence: 61%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) 20Efu/J × Sod2 tm1Smel , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

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“…The latter was further supported by observation of correlation between ROS concentration and degree of keratinocyte differentiation (41,42). We therefore hypothesized that eTRPM8-dependent production of both ATP and O…”

Section: Suppresses Omentioning

confidence: 63%

Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner

Bidaux

Borowiec

Gordienko

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Deviation of the ambient temperature is one of the most ubiquitous stimuli that continuously affect mammals' skin. Although the role of the warmth receptors in epidermal homeostasis (EH) was elucidated in recent years, the mystery of the keratinocyte mild-cold sensor remains unsolved. Here we report the cloning and characterization of a new functional epidermal isoform of the transient receptor potential M8 (TRPM8) mild-cold receptor, dubbed epidermal TRPM8 (eTRPM8), which is localized in the keratinocyte endoplasmic reticulum membrane and controls mitochondrial Ca 2+ concentration ([Ca 2+ ] m ). In turn, [Ca 2+ ] m modulates ATP and superoxide (O •−2 ) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and O •−2 levels by cooling controls the balance between keratinocyte proliferation and differentiation. Finally, to ascertain eTRPM8's role in EH in vivo we developed a new functional knockout mouse strain by deleting the pore domain of TRPM8 and demonstrated that eTRPM8 knockout impairs adaptation of the epidermis to low temperatures.he skin epidermis provides a protective barrier that guards the body against an uncongenial environment. Under the influence of a variety of ambient factors the skin epidermis undergoes continuous regeneration through so-called epidermal homeostasis (EH): the fine-tuning of the balance between proliferation, directional migration, differentiation, and death of keratinocytes. EH involves complex molecular and chemical pathways, regulating dynamic and continuous transition of keratinocytes from the proliferating state in the basal layer to the nonproliferating state in the suprabasal layer before the beginning of the differentiation in the stratum spinosum and stratum granulosum. The terminal differentiation step, characterized by keratinocyte death, transforms keratinocytes into corneocytes, which form the waterproof, mechanically resistant sheath of the stratum corneum (1).Deviation of the ambient temperature is one of the most important stimuli that constantly affect mammals' skin. At ambient temperatures from +10°C to +30°C, the unprotected human skin temperature settles at mean steady-state values within the range of +24°C to +33°C, respectively (2). Temperature is perceived by thermoreceptors, the ion channels that belong to the transient receptor potential (TRP) superfamily (for review see ref.3). Of these, TRPV1 and TRPV2 are activated by heat (above 42°C and above 52°C, respectively) (4), whereas TRPM8 and likely TRPA1 are activated by mild (5, 6) and noxious (7-9) cold, respectively. Heatstimulated keratinocytes have been shown to secrete ATP (10) and, taking into account that purinergic receptors are expressed in keratinocytes (11), TRPV3 is involved in a paracrine heat-

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Induction of Apoptosis-Like Mitochondrial Impairment Triggers Antioxidant and Bcl-2-Dependent Keratinocyte Differentiation

Cited by 33 publications

References 56 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner

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