Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation
Abstract
Serum and glucocorticoid regulated kinase 1 (Sgk1) is a serine-threonine kinase that is activated by serum, steroids, insulin, vasopressin, and interleukin 2 at the transcriptional and post-translational levels. Sgk1 is also important in transduction of growth factors and steroid-dependent survival signals and may have a role in the development of resistance to cancer chemotherapy. In the present paper, we demonstrate that Sgk1 activates MDM2-dependent p53 ubiquitylation. The results were obtained in RKO cells and other cell lines by Sgk1-specific RNA silencing and were corroborated in an original mouse model as well as in transiently and in stably transfected HeLa cells expressing wild-type or dominant negative Sgk1 mutant. Sgk1 contributes to cell survival, cell-cycle progression, and epithelial de-differentiation. We also show that the effects of Sgk1 on the clonogenic potential of different cancer cells depend on the expression of wild-type p53. Since transcription of Sgk1 is activated by p53, we propose a finely tuned feedback model where Sgk1 down-regulates the expression of p53 by enhancing its mono- and polyubiquitylation.
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SGK1 influences cell growth, proliferation, survival, migration, and apoptosis.
“Moreover, it significantly influences cell growth, proliferation, survival, migration, and apoptosis”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Amato et al., 2009
Cites
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“The protein can be inactivated by ubiquitylation [20, 21].”
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“Based on these recent observations, Sgk1 antagonistic molecules are considered in the experimental therapy of prostatic cancer [ 14 ], a tumor that is also finally regulated by steroid hormones [15].”
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“SGK1 phosphorylates MDM2 at Ser-166/186, the same sites phosphorylated by AKT, to activate MDM2 [97,99], which in turn down-regulates p53 function.”
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“, 2006) and stimulates proliferation (Amato et al., 2009; Fagerli et al., 2011; Zhong et al., 2014).”
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“As a nuclear-localized E3 ubiquitin ligase, MDM2 can promote tumor formation by targeting tumor suppressor protein p53 and mediating its ubiquitination [30, 31].”
BackgroundSGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway
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“And similar results were observed in a synchronised HeLa continuous cell line, the inhibition of SGK1 by its dominant negative mutant caused a striking delay in the G2/M-phase entry (Amato et al, 2009).”
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“SGK1 stimulates ubiquitylation and proteosomal degradation of the transcription factor p53.(40) SGK1”
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Eylenstein, A., Gehring, E., Heise, N., Shumilina, E. V., Schmidt, S., Szteyn, K., Münzer, P., Nurbaeva, M. K., Eichenmüller, M., Tyan, L., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-178210 · Cited by 88 · see citing works
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“SGK1 expression regulation by several transcriptional activators, such as mTOR (19, 66, 116–118), AR (45, 51, 119–121), PI3K (53, 122, 123), GR (45, 60, 98, 120, 124), Wnt/b-catenin (45, 125, 126), c-fms (127), Yes-associated transcriptional regulator (YAP) (128), Src (129), progesterone receptor (PR) (130), GINS comp…”
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“SGK1 further supports cell survival by phosphorylating MDM2 leading to MDM2-dependent p53 ubiquitylation with subsequent proteosomal p53 degradation [53].”
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“Infact, SI113-dependent SGK1 inhibition causes cell cycle delay and cell death, which interestingly recapitulates previously described effects of SGK1 silencing in several cancer cell lines [13, 20, 21, 23, 24].”
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“These plasmids were then used to transfect mouse embryonic fibroblasts with a double-knockout of p53 and MDM2 either alone or in combination for related experiments as previously reported 58,59 .”
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BackgroundMethodResultInfluentialSelf-citationSgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells
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“Finally, SGK1 is able to phosphorylate the ubiquitin ligase MDM2 with subsequent MDM2-dependent ubiquitylation and proteosomal degradation of proapoptotic transcription factor p53, stimulating cell proliferation (Amato et al., 2009).”
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“Previous studies have demonstrated that SGK1 regulates cell survival, proliferation and differentiation through MDM2 or p53 [40, 41].”
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“factors, p53 (7), and mammalian target of rapamycin”
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“The SGK1-dependent post-translational regulation of p53 demonstrated that SGK1 is able to regulate MDM2 [9,10].”
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“Previous studies have demonstrated that suppression of SGK1 activity, either by silencing or through use of specific inhibitors, results in apoptosis and cell cycle arrest in several cancer cell lines, suggesting the essential role of SGK1 in survival and proliferation of malignant tumor cells.(27,28,43) Our results r…”
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Self-citationTo die or not to die SGK1-sensitive ORAI/STIM in cell survival
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“Several mechanisms, such as mTOR, FOXO3a, β-catenin, p53 and NF-kB, have been reported or predicted to be involved in SGK1dependent tumor cell proliferation and tumor growth [19-25].”
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Self-citationAudia, S., Brescia, C., Dattilo, V., D'Antona, L., Calvano, P., Iuliano, R., Trapasso, F., Perrotti, N., & Amato, R. (2023) · Cancers · doi:10.3390/cancers15020486 · Cited by 21
“This chapter develops from the evidence that the stress kinase SGK1 (serum- and glucocorticoid-regulated kinase 1) [51] implicated in neoplastic initiation and deregulation, through its ability to block several apoptotic pathways [52], mediate EMT processes and induce loss of cellular genomic control through MDM2-depe…”
Self-citationMachado, R. A. C., Stojevski, D., Landtsheer, S. D., Lucarelli, P., Baron, A., Sauter, T., & Schaffner‐Reckinger, E. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00710-5 · Cited by 15 · see citing works
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“Moreover, these data are consistent with the effects of SGK1, the principal target of SI113, on epithelial dedifferentiation, as previously demonstrated by SGK1 silencing/overexpression in epithelial cells (Amato et al., 2009).”
ResultSelf-citationHe, S.-L., Zhang, H.-L., Xiao, Z.-W., Bhushan, S., Gao, K., & Wang, W.-P. (2021) · Bioengineered · doi:10.1080/21655979.2021.1882142 · Cited by 15
The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium
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Self-citationPhospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway
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Response of human non-small-cell lung cancer cells to the influence of Wogonin with SGK1 dynamics
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Self-citationSuccessful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro
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“3A, B. SGK1 codes for a protein that is involved in cell growth, survival, migration and the cellular stress response (Amato et al., 2009).”
BackgroundBerdel, H. O., Yin, H., Liu, J. Y., Grochowska, K., Middleton, C., Yanasak, N. E., Abdelsayed, R. A., Berdel, W. E., Mozaffari, M. S., Yu, J. C.-K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113795 · Cited by 14 · see citing works
“Interestingly, SGK-1 has further been implicated in downregulating the pro-apoptotic transcription factor p53 by activating its ubiquitination and thereby degradation [14].”
BackgroundSerum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
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“For instance, serum and glucocorticoid regulated kinase 1 (Sgk1) has been shown to phosphorylate human Mdm2-S166 and - S188 (Amato et al., 2009).”
Background
- Authors
- Amato, R., D’Antona, L., Porciatti, G., Agosti, V., Menniti, M., Rinaldo, C., Costa, N., Bellacchio, E., Mattarocci, S., Fuiano, G., Soddu, S., Paggi, M. G., Lang, F., & Perrotti, N.
- Affiliations
- Magna Graecia University (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
- University of Tübingen (DE)
- Corresponding author
- Perrotti, Nicola
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2009-09-11
- Volume
- 87
- Issue
- 12
- Pages
- 1221-1239
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W2121058265
- Cited by
- 103
- References
- 0
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 5 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 14 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 8
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- SGK1, MDM2, p53 degradation, cell proliferation, cell survival, epithelial dedifferentiation, cell cycle progression, clonogenicity, cancer chemotherapy resistance
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Animals, Cell Differentiation, Cell Line, Cell Survival, HeLa Cells, Humans, Male, Mice, Inbred BALB C, Mice, Transgenic, Transfection, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cell Death, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Cell Proliferation, Mice, Proto-Oncogene Proteins c-mdm2
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