Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator

Zhou, Xiang; Hao, Qian; Liao, Peng; Luo, Shuhong; Zhang, Min-Hong; Hu, Guohui; Liu, Hongbing; Zhang, Yiwei; Cao, Bo; Baddoo, Melody; Flemington, Erik K.; Zeng, Shelya X.; Lu, Hua

doi:10.7554/elife.15099

Cited by 66 publications

(62 citation statements)

References 73 publications

(122 reference statements)

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“…Both NGF and BDNF have already been shown to promote tumor innervation in other tissues [29,72,74,79]. In addition to promoting cancer innervation, neurotrophin-mediated signaling has been shown to directly drive tumor onset and progression [72,74,[80][81][82]. The neurotrophin receptors TRKA, TRKB, and P75/NGFR are expressed by malignant cells in many tumor types, where they inhibit key tumor suppressor mechanisms [82] or directly promote cancer cell proliferation and invasiveness [71,74,80,81,83].…”

Section: Discussionmentioning

confidence: 99%

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

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Ameloblastomas are locally invasive and aggressive odontogenic tumors treated via surgical resection, which results in facial deformity and significant morbidity. Few studies have addressed the cellular and molecular events of ameloblastoma onset and progression, thus hampering the development of non-invasive therapeutic approaches. Tumorigenesis is driven by a plethora of factors, among which innervation has been long neglected. Recent findings have shown that innervation directly promotes tumor progression. On this basis, we investigated the molecular characteristics and neurotrophic properties of human ameloblastomas. Our results showed that ameloblastomas express dental epithelial stem cell markers, as well as components of the Notch signaling pathway, indicating persistence of stemness. We demonstrated that ameloblastomas express classical stem cell markers, exhibit stem cell potential, and form spheres. These tumors express also molecules of the Notch signaling pathway, fundamental for stem cells and their fate. Additionally, we showed that ameloblastomas express the neurotrophic factors NGF and BDNF, as well as their receptors TRKA, TRKB, and P75/NGFR, which are responsible for their innervation by trigeminal axons in vivo. In vitro studies using microfluidic devices showed that ameloblastoma cells attract and form connections with these nerves. Innervation of ameloblastomas might play a key role in the onset of this malignancy and might represent a promising target for non-invasive pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pagella

Catón

Meisel

et al. 2020

Cells

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“…Interestingly, besides MDMX, other proteins have been suggested to modulate Mdm2-mediated p53 ubiquitination and degradation, including Yin-Yang1 (ref. 10), gankyrin11, Daxx12 and our recently identified NGFR13. However, it remains to be found out if there are still more yet unidentified regulators of this feedback loop.…”

mentioning

confidence: 85%

Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53

et al. 2016

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The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers.

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“…p53 also exerts its tumor suppressive role via upregulating miR-139-5p, subsequently to inactivate oncoprotein PDE4D in xenograft colorectal carcinoma models [190]. Recently, nerve growth factor receptor (NGFR), the novel inactivator and downstream target of p53, has been characterized to inhibit tumor suppressor function of p53 in glioblastoma, lead to reduced apoptosis and enhanced migratory capability [191]. Hence, targeted p53 strategy seems to be a promising therapeutic option among patients refractory to routine treatments, either by p53 activator such as APR-246 or exogenous p53 supplements.…”

Section: Functions Of Ampk Signaling Components In Tumorigenesismentioning

confidence: 99%

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

Cheng

Zhang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.

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Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator

Cited by 66 publications

References 73 publications

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

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