The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Tesoriere, Annachiara; Dinarello, Alberto; Argenton, Francesco

doi:10.3390/biomedicines9080956

Cited by 46 publications

(43 citation statements)

References 99 publications

(191 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Canonical STAT3 activation depends on different modifications, such as the phosphorylation at tyrosine 705 (Y705) that induces dimerisation and translocation to the nucleus, and at serine 727 (S727), the function of which has been reported to have unclear effects on STAT3 nuclear transcriptional activity ( Decker and Kovarik, 2000 ; Huang et al, 2014 ; Tesoriere et al, 2021 ). On the other hand, the post-translational modifications required for mitoSTAT3 import and activity in mitochondria have not been clearly dissected so far, although phosphorylation at S727 has been found to both activate OXPHOS complexes I and II, and suppress ROS production and cytochrome c release following ischemic injury ( Meier and Larner, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

et al. 2021

Self Cite

View full text Add to dashboard Cite

The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity affects their proliferation rates. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. These data were confirmed using mouse embryonic stem cells: while the Y705 mutated STAT3 cannot enter mitochondria, the S727 mutation does not affect the import in the organelle and is responsible for STAT3-dependent mitochondrial transcription. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to STAT3 responsive elements. Finally, loss of function experiments, with chemical inhibition of the JAK/STAT3 pathway or genetic ablation of stat3 gene, demonstrated that STAT3 is also required for cell proliferation in the intestine of zebrafish.

show abstract

Section: Discussionmentioning

confidence: 99%

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…STAT3 can be phosphorylated by an array of membrane receptors or cytoplasmic tyrosine kinases; in LNCaP cells, β-HCH was found to activate STAT3 via the SRC/STAT3 axis [ 17 ]. As a transcription factor, STAT3 directly regulates the expression of a wide range of oncogenic genes [ 61 ]. Taking into account that a good part of TOBC components is active towards STAT3 [ 62 ], it is conceivable to hypothesize that TOBC could counteract β-HCH-induced STAT3 phosphorylation and nuclear translocation.…”

Section: Resultsmentioning

confidence: 99%

Tomato and Olive Bioactive Compounds: A Natural Shield against the Cellular Effects Induced by β-Hexachlorocyclohexane-Activated Signaling Pathways

et al. 2021

View full text Add to dashboard Cite

The β-isomer of hexachlorocyclohexane (β-HCH) is a globally widespread pollutant that embodies all the physicochemical characteristics of organochlorine pesticides, constituting an environmental risk factor for a wide range of noncommunicable diseases. Previous in vitro studies from our group disclosed the carcinogenic potential of β-HCH, which contributes to neoplastic transformation by means of multifaceted intracellular mechanisms. Considering the positive evidence regarding the protective role of natural bioactive compounds against pollution-induced toxicity, micronutrients from olive and tomato endowed with the capability of modulating β-HCH cellular targets were tested. For this purpose, the solution obtained from a patented food supplement (No. EP2851080A1), referred to as Tomato and Olive Bioactive Compounds (TOBC), was administered to the androgen-sensitive prostate cancer cells LNCaP and different biochemical and cellular assays were performed to evaluate its efficiency. TOBC shows a dose-dependent significant chemoprotection by contrasting β-HCH-induced intracellular responses such as STAT3 and AhR activation, disruption of AR signaling, antiapoptotic and proliferative activity, and increase in ROS production and DNA damage. These experimental outcomes identified TOBC as a suitable functional food to be included in a diet regimen aimed at defending cells from β-HCH negative effects, recommending the development of tailored enriched formulations for exposed individuals.

show abstract

“…A prerequisite for STAT3 transcriptional activity is its phosphorylation. The phosphorylation on tyrosine 705 is a crucial event triggering the transcription of many STAT3 target genes, although another phosphorylation site is the serine 727 residue [30].…”

Section: Salviolone and Cryptotanshinone Affect Pro-survival Pathways In The A375 Cell Linementioning

confidence: 99%

Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation

Zanrè

Campagnari

Cerulli

et al. 2022

IJMS

View full text Add to dashboard Cite

Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects. Seven diterpenoid derivatives were purified from S. miltiorrhiza roots and identified by NMR and MS analysis. Tanshinone IIA and cryptotanshinone were detected as the main components of S. miltiorrhiza root ethanol extract. Although their antitumor activity is already known, they have been confirmed to induce a reduction in A375 and MeWo melanoma cell growth. Likewise, salviolone has been shown to impair the viability of melanoma cells without affecting the growth of normal melanocytes. The underlying anticancer activity of salviolone has been investigated and compared to that of cryptotanshinone in A375 cells, showing an increased P21 protein expression in a P53-dependent manner. In that way, salviolone, even more than cryptotanshinone, displays a multitarget effect on cell-cycle-related proteins. Besides, it modulates the phosphorylation level of the signal transducer and activator of transcription (STAT)3. Unexpectedly, salviolone and cryptotanshinone induce sustained activation of the extracellular signal-regulated kinases (ERK)1/2 and the protein kinase B (Akt). However, the blockage of ERK1/2 or Akt activities suggests that kinase activation does not hinder their ability to inhibit A375 cell growth. Finally, salviolone and cryptotanshinone inhibit to a comparable extent some crucial malignancy features of A375 melanoma cells, such as colony formation in soft agar and metalloproteinase-2 activity. In conclusion, it has been shown for the first time that salviolone, harboring a different molecular structure than tanshinone IIA and cryptotanshinone, exhibits a pleiotropic effect against melanoma by hampering cell cycle progression, STAT3 signaling, and malignant phenotype of A375 melanoma cells.

show abstract

The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Cited by 46 publications

References 99 publications

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

Tomato and Olive Bioactive Compounds: A Natural Shield against the Cellular Effects Induced by β-Hexachlorocyclohexane-Activated Signaling Pathways

Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation

Contact Info

Product

Resources

About