Identification of an Interaction between the TPα and TPβ Isoforms of the Human Thromboxane A2 Receptor with Protein Kinase C-related Kinase (PRK) 1

Turner, Elizebeth C.; Kavanagh, David J.; Mulvaney, Eamon P.; McLean, Caitriona; Wikström, Katarina; Reid, Helen M.; Kinsella, B. Thérèse

doi:10.1074/jbc.m110.181180

Cited by 29 publications

(46 citation statements)

References 60 publications

(94 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Added to this complexity, we recently established that the TPα and TPβ isoforms differentially associate with and regulate signalling by the other individual members of the PRKs (PRK1/PKNα, PRK2/PKNγ, PRK3/PKNβ) (57). Furthermore, consistent with our previous studies involving PRK1 (48), siRNA disruption of PRK1 and PRK2, but not PRK3, expression eliminates TP-mediated cancer cell responses (proliferation, anchorage-independent growth, migration) and H3pThr11 phosphorylation in the prostate carcinoma PC-3 cell line (57). Identification of a direct, functional interaction of both TPα and TPβ with the PRKs provides yet another molecular link accounting for the role of TXA 2 in tumour progression, particularly in prostate and other cancers in which the TXA 2 -TP and PRKs are increasingly implicated.…”

Section: The Role Of Thromboxane In Cancersupporting

confidence: 82%

“…Indeed, our research shows that TPα-/TPβ-mediated PRK1 activation not only leads to histone H3 threonine 11 phosphorylation in response to TXA 2 but can also cooperate with the AR to enhance the androgen-induced chromatin remodelling (H3pThr11) and transcriptional activation (48). Collectively, these studies raise the exciting possibility that TXA 2 , through its ability to directly regulate PRK-induced H3pThr11, may be a strong epigenetic regulator, thereby adding to the range of possible mechanisms, whereby the Aspirin-target TXA 2 may influence the neoplastic growth.…”

Section: The Role Of Thromboxane In Cancermentioning

confidence: 99%

“…Significantly in the context of PCa, through detailed mechanistic studies, we recently discovered that both the TPα and the TPβ isoforms directly interact with and regulate signalling by protein kinase C-related kinase/ protein kinase novel (PRK/PKN) (48), a family of 3 AGC kinases that act immediately downstream of phosphatidylinositol 3′kinases, and are strongly, yet differentially, implicated in several cancers (49)(50)(51) and in B-cell development (52). Indeed, in addition to acting as Rho GTPase effectors, activation of the PRKs (e.g., PRK1) in response to androgen receptor (AR) signalling within the prostate catalyses phosphorylation of histone (H)3 at Thr11 (H3pThr11) which, in turn, serves as a specific epigenetic marker, and gatekeeper, of androgen-induced chromatin remodelling and transcriptional activation (48,(53)(54)(55). Hence, owing to their ability to regulate RhoA-/C-mediated responses, including metastatic processes, combined with their epigenetic priming of tumour cells, members of the PRK family are key chemotherapeutic targets particularly in castrate-resistant prostate cancer, the metastatic lethal form of PCa that occurs following androgen deprivation therapy (53,55,56).…”

Section: The Role Of Thromboxane In Cancermentioning

confidence: 99%

See 2 more Smart Citations

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Kinsella

2016

Wilms Tumor

Self Cite

View full text Add to dashboard Cite

Copyright: The Author.Licence: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the author and the publisher are explicitly identified and properly acknowledged as the original source. AbstractThe prostanoid thromboxane (TX)A 2 plays a fundamental role in vascular haemostasis and, more recently, is increasingly implicated in various neoplasms including in prostate, breast and bladder cancers, among others. In humans, TXA 2 signals through the TPα and TPβ isoforms of the T prostanoid receptor (TP), two structurally related receptors that display both common, over-lapping but also distinct, isoform-specific physiologic roles. Consistent with this, while TPα and TPβ are encoded by the same gene, the TBXA2R, they are Kinsella 164 differentially expressed due to their transcriptional regulation by distinct promoters where promoter (Prm) 1 regulates TPα expression and Prm3 regulates TPβ. While the clinical evidence for the role of the TXA 2 -TP axis in neoplastic progression is increasing, few studies to date have investigated the role of the individual TPα/TPβ isoforms in human cancer or indeed in most other diseases in which the TXA 2 -TP axis is implicated. Focusing on TPα, this review details the current understanding of the factors regulating its expression and transcriptional regulation through Prm1, including in prostate and breast cancers. Emphasis is placed on the trans-acting transcriptional regulators that bind to cis-elements within the core and upstream regulatory regions of Prm1 under basal conditions and in response to cellular differentiation. A particular focus is placed on the role of the tumour suppressor Wilms' tumour 1 in the regulation of TPα expression through Prm1 in megakaryoblastic cells of vascular origin and in prostate and breast carcinoma cells. Collectively, this review details current knowledge of the factors determining regulation of the TXA 2 -TPα axis and thereby provides a genetic basis for understanding the role of TXA 2 in the progression of certain human cancers.

show abstract

Section: The Role Of Thromboxane In Cancersupporting

confidence: 82%

Section: The Role Of Thromboxane In Cancermentioning

confidence: 99%

Section: The Role Of Thromboxane In Cancermentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Kinsella

2016

Wilms Tumor

Self Cite

View full text Add to dashboard Cite

show abstract

“…A recent report provided evidence of a novel constitutive interaction between TPα/TPβ and protein kinase C-related kinases (PRK1) [51]. PRK1 is a Rho-A effector that has been widely implicated in androgen-associated PCas and ovarian serous carcinomas [51].…”

Section: Role Of Thromboxane A2 and Its Receptors In Cancer Progresmentioning

confidence: 99%

The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis

Ekambaram

Lambiv

Cazzolli

et al. 2011

Cancer Metastasis Rev

View full text Add to dashboard Cite

Thromboxane A2 (TXA2) is a biologically active metabolite of arachidonic acid formed by the action of the terminal synthase, thromboxane A2 synthase (TXA2S), on prostaglandin endoperoxide (PGH2). TXA2 is responsible for multiple biological processes through its cell surface receptor, the T-prostanoid (TP) receptor. Thromboxane A2 synthase and TP are the two necessary components for the functioning of this potent bioactive lipid. Thromboxane A2 is widely implicated in a range of cardiovascular diseases, owing to its acute and chronic effects in promoting platelet aggregation, vasoconstriction, and proliferation. In recent years, additional functional roles for both TXA2S and TP in cancer progression have been indicated. Increased cyclooxygenase (COX)-2 expression has been described in a variety of human cancers, which has focused attention on TXA2 as a downstream metabolite of the COX-2-derived PGH2. Several studies suggest potential involvement of TXA2S and TP in tumor progression, especially tumor cell proliferation, migration, and invasion that are key steps in cancer progression. In addition, the regulation of neovascularization by TP has been identified as a potent source of control during oncogenesis. There have been several recent reviews of TXA2S and TP but thus far none have discussed its role in cancer progression and metastasis in depth. This review will focus on some of the more recent findings and advances with a significant emphasis on understanding the functional role of TXA2S and TP in cancer progression and metastasis.

show abstract

“…The TXA 2 ligand, in turn, activates the TP receptor, promoting cell migration, proliferation, and invasion, which are key hallmarks of cellular transformation and the progression of disease [3], [4], [5], [6], [7]. Other studies have indicated a role for TXA 2 signalling in the tumorigenesis and malignant phenotypes of prostate [8] and breast cancers [9], [10].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Tumor Suppressor FOXO3 by the Thromboxane-A2 Receptors in Urothelial Cancer

Sobolesky¹,

Halushka²,

Garrett‐Mayer³

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

The transcription factor FOXO3 is a well-established tumor suppressor whose activity, stability, and localization are regulated by phosphorylation and acetylation. Previous data by our laboratory demonstrated amplified thromboxane-A2 signaling was associated with poor prognoses in bladder cancer patients and overexpression of the thromboxane-A2 isoform-β receptor (TPβ), but not TPα, induced malignant transformation of immortalized bladder cells in vivo. Here, we describe a mechanism of TP mediated modulation of FOXO3 activity and localization by phosphorylation and deacetylation in a bladder cancer cell model. In vitro gain and loss of function studies performed in non-transformed cell lines, UROsta and SV-HUC, revealed knockdown of FOXO3 expression by shRNA increased cell migration and invasion, while exogenously overexpressing TPβ raised basal phosphorylated (p)FOXO3-S294 levels. Conversely, overexpression of ERK-resistant, mutant FOXO3 reduced increases in UMUC3 cell migration and invasion, including that mediated by TP agonist (U46619). Additionally, stimulation of UMUC3 cells with U46619 increased pFOXO3-S294 expression, which could be attenuated by treatment with a TP antagonist (PTXA2) or ERK inhibitor (U0126). Initially U46619 caused nuclear accumulation of pFOXO3-S294; however, prolonged stimulation increased FOXO3 cytoplasmic localization. U46619 stimulation decreased overall FOXO3 transcriptional activity, but was associated with increased expression of its pro-survival target, manganese superoxide dismutase. The data also shows that TP stimulation increased the expression of the histone deacetylase, SIRT1, and corresponded with decreased acetylated-FOXO3. Collectively, the data suggest a role for TP signaling in the regulation of FOXO3 activity, mediated in part through phosphorylation and deacetylation.

show abstract

Identification of an Interaction between the TPα and TPβ Isoforms of the Human Thromboxane A2 Receptor with Protein Kinase C-related Kinase (PRK) 1

Abstract: In humans, thromboxane (TX)A

Cited by 29 publications

References 60 publications

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis

Regulation of the Tumor Suppressor FOXO3 by the Thromboxane-A2 Receptors in Urothelial Cancer

Contact Info

Product

Resources

About