The Expression of the Endogenous mTORC1 Inhibitor Sestrin 2 Is Induced by UVB and Balanced with the Expression Level of Sestrin 1

Abstract

Sestrin 2 (SESN2) is an evolutionarily conserved regulator of mechanistic target of rapamycin complex 1 (mTORC1) which controls central cellular processes such as protein translation and autophagy. Previous studies have suggested that SESN2 itself is subjected to regulation at multiple levels. Here, we investigated the expression of SESN2 in the skin and in isolated skin cells. SESN2 was detected by immunofluorescence analysis in fibroblasts and keratinocytes of human skin. Differentiation of epidermal keratinocytes was not associated with altered SESN2 expression and siRNA-mediated knockdown of SESN2 did not impair stratum corneum formation in vitro. However, SESN2 was increased in both cell types when the expression of its paralog SESN1 was blocked by siRNA-mediated knock down, indicating a compensatory mechanism for the control of expression. Irradiation with UVB but not with UVA significantly increased SESN2 expression in both keratinocytes and fibroblasts. Upregulation of SESN2 expression could be completely blocked by suppression of p53. These results suggest that SESN2 is dispensable for normal epidermal keratinization but involved in the UVB stress response of skin cells.

Immunohistochemical evaluation of stress-responsive protein sestrin2 and its correlation with p53 mutational status in eyelid sebaceous gland carcinoma

“…Recent studies have implicated Sestrin2 as a P53 target gene and have been shown to be upregulated during ultraviolet B (UVB) stress response of skin cells 24. In the present study, sestrin2 was found to be downregulated in 55% of SGC cases relative to non-cancerous and adjacent normal skin.…”

Interactions between microRNA-200 family and Sestrin proteins in endometrial cancer cell lines and their significance to anoikis

“…Sestrins belong to conserved stress-responsive proteins regulated by various conditions including hypoxia, oxidative stress, or DNA damage [6, 10]. Physiologically, activated sestrins suppress oxidative stress by reduction of ROS level and inhibition of a mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway [29].…”

“…SESN1 functions as an antioxidant by the regeneration of overoxidized peroxiredoxins [9]. Another member of Sestrin protein family, SESN2 is expressed under different stress conditions as genotoxic stress, oxidative stress, mitochondrial dysfunction, or endoplasmic reticulum stress [10]. SESN2 shares significant homology to SESN1 and both of them belong to growth arrest and DNA damage-inducible family protein (GADD).…”

The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis

“…The top three drivers of this result were genes encoding growth factor receptor-bound protein 10 (GRB10), unc-51 like autophagy-activating kinase 2 (ULK2), and sestrin 2 (SESN2) (supplementary Table 1). Upregulation of these three genes is associated with diminished mTORC1 activity, since GRB10 and SESN2 are negative regulators of the mTORC1 signaling pathway (49, 50), while ULK2, which promotes autophagy (51), is downregulated by mTORC1 (52). In addition, pathways expressing functions that require mTORC1 activation, such as ribosome biogenesis and hypoxia factor 1 alpha (HIF1A)-bound genes (HIF1A activity is induced by mTORC1 (53)), were reduced by simvastatin treatment, while insulin-receptor signaling, which is inhibited by mTORC1 (54), was found upregulated in simvastatin-treated cells.…”