Identification of novel regulators of STAT3 activity

Parri, Elina; Kuusanmäki, Heikki; Adrichem, Arjan J. van; Kaustio, Meri; Wennerberg, Krister

doi:10.1371/journal.pone.0230819

Cited by 16 publications

(10 citation statements)

References 58 publications

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“…It is required for progression through the G1 phase of the cell cycle and protects cells from UV-induced apoptosis. Mutations in the contact region of STAT3 both reduce c-Jun–STAT3 protein interaction and disrupt the cooperation between these two proteins, which is required for maximal IL-6-dependent gene activation driven by the α2-macroglobulin enhancer [ 61 , 63 ]. c-Fos encodes a 62 kDa protein, which forms a heterodimer with c-Jun, resulting in the formation of the AP-1 (activator protein-1) complex, which binds DNA at AP-1 specific sites.…”

Section: Role Of Stat3 In Oncogenic Transformationmentioning

confidence: 99%

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

Tolomeo

Cascio

2021

IJMS

169

105

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Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type.

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Section: Role Of Stat3 In Oncogenic Transformationmentioning

confidence: 99%

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

Tolomeo

Cascio

2021

IJMS

169

105

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“…Indeed, we previously found that JAK2 mRNA is m 6 A-modified during the type I IFN response [5]. However, as FTO depletion may regulate the expression of multiple kinases or phosphatases that control STAT3 phosphorylation [47], additional targeted studies will be required for a more complete understanding of the mechanisms by which FTO regulates STAT3 activation.…”

Section: Discussionmentioning

confidence: 99%

FTO suppresses STAT3 activation and modulates proinflammatory interferon-stimulated gene expression

McFadden

Sacco

Murphy

et al. 2021

Preprint

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Signaling initiated by type I interferon (IFN) results in the induction of hundreds of IFN-stimulated genes (ISGs). The type I IFN response is important for antiviral restriction, but aberrant activation of this response can lead to inflammation and autoimmunity. Regulation of this response is incompletely understood. We previously reported that the mRNA modification m6A and its deposition enzymes, METTL3 and METTL14 (METTL3/14), promote the type I IFN response by directly modifying the mRNA of a subset of ISGs to enhance their translation. Here, we determined the role of the RNA demethylase FTO in the type I IFN response. FTO, which can remove either m6A or the cap-adjacent m6Am RNA modifications, has previously been associated with obesity and body mass index, type 2 diabetes, cardiovascular disease, and inflammation. We found that FTO suppresses the transcription of a distinct set of ISGs, including many known pro-inflammatory genes, and that this regulation is not through the actions of FTO on m6Am. Further, we found that depletion of FTO led to activation of STAT3, a transcription factor that mediates responses to various cytokines, but whose role in the type I IFN response is not well understood. This activation of STAT3 increased the expression of a subset of ISGs. Importantly, this increased ISG induction resulting from FTO depletion was partially ablated by depletion of STAT3. Together, these results reveal that FTO negatively regulates STAT3-mediated signaling that induces proinflammatory ISGs during the IFN response, highlighting an important role for FTO in suppression of inflammatory genes.

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“…These findings suggest a role for PTPRH in differentiation programs limiting neuroblastoma cell growth, and are consistent with the upregulation of PTPRH expression upon differentiation of other cell types ( Nunes-Xavier et al, 2012 ; Nunes-Xavier et al, 2013 ), as well as with its downregulation in some cancer types ( Nagano et al, 2003 ; Bujko et al, 2017 ). Remarkably, PTPRH was selected in a siRNA screening as a potential STAT3 regulator ( Parri et al, 2020 ), and it has also been found to associate with and dephosphorylate several RTK, including EGFR and IR ( Shintani et al, 2015 ; Yao et al, 2017 ). Since the related PTPRO enzyme, which is mainly expressed in the developing nervous system, dephosphorylates Trk receptors ( Hower et al, 2009 ; Gatto et al, 2013 ), a role is possible for PTPRH in the direct regulation of Trk signaling in neuroblastoma cells.…”

Section: Classical Protein Tyrosine Phosphatases In Neuroblastomamentioning

confidence: 99%

Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

Nunes‐Xavier

Zaldumbide

Mosteiro

et al. 2021

Front. Cell Dev. Biol.

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Neuroblastoma is a type of cancer intimately related with early development and differentiation of neuroendocrine cells, and constitutes one of the pediatric cancers with higher incidence and mortality. Protein tyrosine phosphatases (PTPs) are key regulators of cell growth and differentiation by their direct effect on tyrosine dephosphorylation of specific protein substrates, exerting major functions in the modulation of intracellular signaling during neuron development in response to external cues driving cell proliferation, survival, and differentiation. We review here the current knowledge on the role of PTPs in neuroblastoma cell growth, survival, and differentiation. The potential of PTPs as biomarkers and molecular targets for inhibition in neuroblastoma therapies is discussed.

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Identification of novel regulators of STAT3 activity

Cited by 16 publications

References 58 publications

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy

FTO suppresses STAT3 activation and modulates proinflammatory interferon-stimulated gene expression

Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

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