ATF-2 and Tpl2 regulation of endothelial cell cycle progression and apoptosis

Fearnley, Gareth W.; Latham, Antony M.; Hollstein, Monica; Odell, Adam F.; Ponnambalam, Sreenivasan

doi:10.1016/j.cellsig.2019.109481

“…However, TPL2 protein might positively induce cell cycle arrest and apoptosis by promoting the accumulation of cell cycle inhibitor and pro-apoptotic proteins such as BCL2-associated X protein (BAX), p21 and p53 in a context-dependent manner 41 , 57 , 58 . Knockdown of ATF2, a transcription factor that negatively regulates expression of cell cycle inhibitor p21 and p53, was shown to induce the expression of TPL2, p53 and p21, while simultaneous depletion of ATF2 and TPL2 suppressed p53 and p21 expression 58 . The study indicates that the TPL2 protein is involved in the positive regulation of p53 and p21 expression, and the subsequent induction of cell cycle arrest.…”

Section: Tpl2 and Tumorigenesismentioning

confidence: 99%

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Njunge¹,

Estania²,

Guo³

et al. 2020

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Over the years, tumor progression locus 2 (TPL2) has been identified as an essential modulator of immune responses that conveys inflammatory signals to downstream effectors, subsequently modulating the generation and function of inflammatory cells. TPL2 is also differentially expressed and activated in several cancers, where it is associated with increased inflammation, malignant transformation, angiogenesis, metastasis, poor prognosis and therapy resistance. However, the relationship between TPL2-driven inflammation, tumorigenesis and tumor immunity has not been addressed. Here, we reconcile the function of TPL2-driven inflammation to oncogenic functions such as inflammation, proliferation, apoptosis resistance, angiogenesis, metastasis, immunosuppression and immune evasion. We also address the controversies reported on TPL2 function in tumor-promoting inflammation and tumorigenesis, and highlight the potential role of the TPL2 adaptor function in regulating the mechanisms leading to pro-tumorigenic inflammation and tumor progression. We discuss the therapeutic implications and limitations of targeting TPL2 for cancer treatment. The ideas presented here provide some new insight into cancer pathophysiology that might contribute to the development of more integrative and specific anti-inflammatory and anti-cancer therapeutics.

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“…The accumulated HIF-2α is associated with the constitutively expressed HIF-1β to form a heterodimer, which is then transferred to the nucleus. Subsequently, the expression of the downstream genes, vascular endothelial growth factor A (VEGFA) and cyclin D1 (CCND1) [16], is activated, and several physiological processes, such as angiogenesis, cell metabolism, cell proliferation, and cell apoptosis are regulated [17][18][19]. VHL mutations are observed in ~70-80% of ccRCC [20], and the Cullin2-VHL E3 ubiquitin ligase complex cannot be formed, resulting in the stabilization of the HIF-2α protein irrespective of the cellular oxygen supply [21].…”

Section: Introductionmentioning

confidence: 99%

VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression

Ji¹,

Xu²,

Xie³

et al. 2023

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SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/β-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent β-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/β-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/β-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.

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“…The accumulated HIF-2α is associated with the constitutively expressed HIF-1β to form a heterodimer, which is then transferred to the nucleus. Subsequently, the expression of the downstream genes, vascular endothelial growth factor A (VEGFA) and cyclin D1 (CCND1) 16 , is activated, and several physiological processes, such as angiogenesis, cell metabolism, cell proliferation, and cell apoptosis are regulated 17,18,19 . VHL mutations are observed in approximately 70-80% of ccRCC 20 , and the Cullin2-VHL E3 ubiquitin ligase complex cannot be formed, resulting in the stabilization of the HIF-2α protein irrespective of the cellular oxygen supply 21 .…”

Section: Introductionmentioning

confidence: 99%

VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression

Ji¹,

Xu²,

Xie³

et al. 2022

Preprint

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SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/β-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent β-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/β-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/β-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.

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ATF-2 and Tpl2 regulation of endothelial cell cycle progression and apoptosis

Abstract: This is a repository copy of ATF-2 and Tpl2 regulation of endothelial cell cycle progression and apoptosis.

Cited by 5 publications

References 34 publications

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression

VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression

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