Senescent Keratinocytes Die by Autophagic Programmed Cell Death

Gosselin, Karo; Deruy, Emeric; Martien, Sébastien; Vercamer, Chantal; Bouali, Fatima; Dujardin, Thibault; Slomianny, Christian; Houel-Renault, Ludivine; Chelli, Fazia; Launoit, Yvan de; Abbadie, Corinne

doi:10.2353/ajpath.2009.080332

Cited by 103 publications

(98 citation statements)

References 69 publications

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“…Several reports have recently described the autophagy process occurring in monolayer cultures of keratinocytes (Aymard et al, 2011;Chatterjea et al, 2011;Deruy et al, 2010;Gosselin et al, 2009;Lee et al, 2011;Silva et al, 2010;Tong et al, 2012;Wang and Levine, 2011;Zhao et al, 2013;Zhou and Münger, 2009). Autophagy is a highly conserved proteolytic mechanism that maintains the homeostasis of the cell by degrading organelles and cytoplasmic material.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…105 A third study demonstrated that senescent keratinocytes seem to die through massive and specific autophagic degradation of their nuclei and mitochondria, although degradation of other cellular organelles was not examined. 106 Other findings supported the role of autophagy in the death of senescent keratinocytes. The autophagy inhibitor 3-methyladenine can delay the death of senescent cells.…”

Section: Autophagic Degradation Of the Nucleus And Its Components Insupporting

confidence: 55%

“…This notion was supported by the altered morphology of the nuclei and mitochondria within the central domain and by the level of DNA degradation observed. 106 It is possible that the nuclei of senescent cells in general could be targeted for autophagy simply because their DNA is damaged, since inhibition of DNA-protein kinase, a nuclear kinase involved in DNA-break signaling, sensitizes to autophagy in malignant glioma cells, 107 suggesting that persistence of damaged DNA can activate the autophagic process. Similarly, both an increase in Beclin-1 (mammalian homologue of Atg6p) expression and a concomitant increase in autophagic activity occur following treatment with the DNA-damaging agent etoposide.…”

Section: A Second Form Of Autophagic Degradation Of the Yeast Nucleusmentioning

confidence: 99%

The intricacy of nuclear membrane dynamics during nucleophagy

Mijaljica

Prescott

Devenish

2010

Nucleus

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The nucleus is a site of a number of essential metabolic activities relating to maintenance and expression of the genome. Such activities include: DNA replication, recombination and repair, gene transcription, RNA processing and ribosome subunit maturation and assembly. 1,2 In order for these essential activities to be carried out in a correct and efficient manner the corresponding machinery must be maintained. Consequently, it is to be expected there are processes within cells which act to 'repair' nuclear damage through the coordinated removal of damaged non-functional components, or those surplus to requirement. A growing body of evidence indicates that parts of the nucleus can be specifically degraded by nucleophagy (micronucleophagy), an autophagic process involving localized changes in membrane organization and dynamics. Here, we discuss nucleophagy in this context as well as its role in 'housecleaning' during nutrient Nuclear Structure, Function and CompartmentalizationThe nucleus is not only the largest membrane-enclosed organelle in eukaryotic cells, but arguably the most elaborate. Two main structures make up the metazoan (including mammalian) nucleus. The first of these is the nuclear envelope (NE) that acts as the interface between the nucleus and the rest of the cell enclosing the contents of the nucleus. 3,4 The second is the nuclear lamina, a dense but fenestrated network composed of intermediate filaments made of lamins and lamin-associated (e.g., emerin) proteins underlying the inner surface of the NE. The NE is required for maintenance of nuclear shape, spacing of nuclear pore complexes (NPCs), organization of heterochromatin, DNA replication and regulation of transcription factors (Fig. 1). [5][6][7][8][9][10][11] Certain organisms, such as fungi or plants lack lamins 12 and consequently lack a nuclear lamina. 13 Plants contain coiled-coil proteins, apparently unrelated to lamins, which serve as nucleoskeleton components.12,14,15 Coiled-coil proteins have been implicated also as nucleoskeleton components in non-metazoans, notably yeast and Trypanosoma brucei. 12,16,17 The NE is comprised of two concentric, closely opposed lipid bilayers, the outer and inner nuclear membranes (ONM and INM, respectively). 4,18 The ONM is continuous with the rough endoplasmic reticulum (rER), studded with ribosomes and functions in secretion and lipid biosynthesis. The ribosome-free INM faces the viscous nucleoplasm, and contains a unique spectrum of integral and membrane-associated proteins that provide binding sites for the nuclear lamina and chromatin. The ONM and INM are separated by a luminal space but become contiguous at sites of high membrane curvature occupied by the NPCs (Fig. 1). NPCs exclusively mediate and regulate nucleocytoplasmic trafficking, the signal-dependent, bidirectional trafficking of macromolecules between the nucleus and cytoplasm which is crucial for both gene expression and chromosomal maintenance. 7,[18][19][20] The interior of the nucleus lacks membrane-bound subcompartments, but is...

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“…Both in vitro and in vivo, as a result of time and cumulative divisions, normal cells enter senescence, characterized by an enlarged morphology, lipofuscin accumulation, increased autophagic activity, cell cycle arrest, and frequent polynucleation (1)(2)(3)(4)(5). It is accepted that senescence results from cumulative oxidative damage and telomere shortening, each probably acting to a different degree according to cell type or environmental conditions.…”

Section: Introductionmentioning

confidence: 99%

Senescence-Associated Oxidative DNA Damage Promotes the Generation of Neoplastic Cells

et al. 2009

Self Cite

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Studies on human fibroblasts have led to viewing senescence as a barrier against tumorigenesis. Using keratinocytes, we show here that partially transformed and tumorigenic cells systematically and spontaneously emerge from senescent cultures. We show that these emerging cells are generated from senescent cells, which are still competent for replication, by an unusual budding-mitosis mechanism. We further present data implicating reactive oxygen species that accumulate during senescence as a potential mutagenic motor of this post-senescence emergence. We conclude that senescence and its associated oxidative stress could be a tumorpromoting state for epithelial cells, potentially explaining why the incidence of carcinogenesis dramatically increases with advanced age. [Cancer Res 2009;69(20):7917-25]

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Senescent Keratinocytes Die by Autophagic Programmed Cell Death

Cited by 103 publications

References 69 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

The intricacy of nuclear membrane dynamics during nucleophagy

Senescence-Associated Oxidative DNA Damage Promotes the Generation of Neoplastic Cells

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