REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids
Abstract Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress‐inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, whi...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2014-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201404601 |
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| author | Gleb Baida Pankaj Bhalla Kirill Kirsanov Ekaterina Lesovaya Marianna Yakubovskaya Kit Yuen Shuchi Guo Robert M Lavker Ben Readhead Joel T Dudley Irina Budunova |
| author_facet | Gleb Baida Pankaj Bhalla Kirill Kirsanov Ekaterina Lesovaya Marianna Yakubovskaya Kit Yuen Shuchi Guo Robert M Lavker Ben Readhead Joel T Dudley Irina Budunova |
| author_sort | Gleb Baida |
| collection | DOAJ |
| description | Abstract Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress‐inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down‐regulation of genes involved in anti‐inflammatory glucocorticoid response was strikingly similar in wild‐type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid‐dependent and glucocorticoid‐independent atrophy. Importantly, the lack of REDD1 did not diminish the anti‐inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid‐based therapies. |
| format | Article |
| id | doaj-art-b03aa1de1a7646688fa6e048f87c7b35 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2014-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b03aa1de1a7646688fa6e048f87c7b352025-08-20T03:43:26ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842014-12-0171425810.15252/emmm.201404601REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoidsGleb Baida0Pankaj Bhalla1Kirill Kirsanov2Ekaterina Lesovaya3Marianna Yakubovskaya4Kit Yuen5Shuchi Guo6Robert M Lavker7Ben Readhead8Joel T Dudley9Irina Budunova10Department of Dermatology, Northwestern UniversityDepartment of Dermatology, Northwestern UniversityN. Blokhin Cancer Research Center, RAMSN. Blokhin Cancer Research Center, RAMSN. Blokhin Cancer Research Center, RAMSDepartment of Dermatology, Northwestern UniversityDepartment of Dermatology, Northwestern UniversityDepartment of Dermatology, Northwestern UniversityDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Dermatology, Northwestern UniversityAbstract Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress‐inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down‐regulation of genes involved in anti‐inflammatory glucocorticoid response was strikingly similar in wild‐type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid‐dependent and glucocorticoid‐independent atrophy. Importantly, the lack of REDD1 did not diminish the anti‐inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid‐based therapies.https://doi.org/10.15252/emmm.201404601glucocorticoidglucocorticoid receptormTORREDD1skin atrophy |
| spellingShingle | Gleb Baida Pankaj Bhalla Kirill Kirsanov Ekaterina Lesovaya Marianna Yakubovskaya Kit Yuen Shuchi Guo Robert M Lavker Ben Readhead Joel T Dudley Irina Budunova REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids EMBO Molecular Medicine glucocorticoid glucocorticoid receptor mTOR REDD1 skin atrophy |
| title | REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| title_full | REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| title_fullStr | REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| title_full_unstemmed | REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| title_short | REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| title_sort | redd1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids |
| topic | glucocorticoid glucocorticoid receptor mTOR REDD1 skin atrophy |
| url | https://doi.org/10.15252/emmm.201404601 |
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