The Unfolded Protein Response Is Activated in Differentiating Epidermal Keratinocytes

Sugiura, Kazumitsu; Muro, Yoshinao; Futamura, Kenta; Matsumoto, Kenji; Hashimoto, Noriko; Nagasaka, Tetsuro; Saito, Hirohisa; Tomita, Yasushi; Usukura, Jiro

doi:10.1038/jid.2009.51

Cited by 72 publications

(85 citation statements)

References 44 publications

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“…Decreased expression of Golgi and ER proteins could be the result of an excessive UPR, a cellular stress response related to the ER that is implicated in both prosurvival responses, by maintaining cellular homeostasis, and in apoptotic cell death, when these responses are not sufficient to relieve ER stress (Kim et al, 2006;Milani et al, 2009). Activation of the UPR has been reported during normal epidermal keratinocyte differentiation (Sugiura et al, 2009). Thus, deregulated UPR activity could be predicted in the absence of iASPP, although further experiments are needed to explore this hypothesis.…”

Section: Discussionmentioning

confidence: 95%

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: Discussionmentioning

confidence: 95%

iASPP is a novel autophagy inhibitor in keratinocytes

Chikh

Sanza

Raimondi

et al. 2014

Journal of Cell Science

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“…Hspa5 is known to regulate differentiation of several cell types, 31 and further evaluation of gastric cell type markers will be required to define the cell lineage origin of Hspa5-expressing metaplastic cells in the mouse. Focal expression of Hspa5 in mouse gastric mucosa is partly attributable to the natural microflora found in SPF mice as lower level of Hspa5 protein was detected in germfree mice.…”

Section: Discussionmentioning

confidence: 99%

The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Baird

Ang

Clark

et al. 2013

Laboratory Investigation

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Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P ¼ 0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa. KEYWORDS: endoplasmic reticulum stress; germfree; mucous metaplasia; unfolded protein response Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC). 1 Sustained interaction between H. pylori and the gastric epithelium induces chronic inflammation and loss of parietal cells (oxyntic atrophy), leading to development of mucous metaplasia (MM)-intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM). 2 Studies in human and murine models indicate that IM and SPEM are critical neoplastic precursors in the cascade of gastric carcinogenesis. [3][4][5][6] IM is characterized by the presence of intestinal goblet cells with simultaneous expressions of TFF3 and MUC2 7 while SPEM, named for its characteristic expression of spasmolytic polypeptide (TFF2), expresses MUC6 and resembles deep antral gland cells. 5 Reported studies suggest that SPEM, derived from transdifferentiation of chief cells, 8 gives rise to IM and ultimately dysplasia in the setting of oxyntic atrophy and chronic inflammation. 9 Despite characterization of the sequence and origin of metaplastic mucous cell lineage, the mechanisms responsible for neoplastic transformation of the secretory cell lineage are not understood.Cancer cells are under constant e...

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“…[28][29][30] Upon differentiation of keratinocytes, e.g., by raising the calcium level with or without the addition of growth factors (EGF and fibroblast growth factor-10) or adding the EGF-receptor inhibitor PD153035, expression of the differentiation-related keratins K1 and K10 are induced in a subpopulation of cells. 28,[30][31][32][33][34][35] …”

Section: Keratin Expression In Normal Human Skin and Cultured Keratinmentioning

confidence: 99%

Regulation of keratin expression by retinoids

Törmä

2011

Dermato-Endocrinology

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The Unfolded Protein Response Is Activated in Differentiating Epidermal Keratinocytes

Cited by 72 publications

References 44 publications

iASPP is a novel autophagy inhibitor in keratinocytes

iASPP is a novel autophagy inhibitor in keratinocytes

The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Regulation of keratin expression by retinoids

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