P53 vs NF-κB: the role of nuclear factor-kappa B in the regulation of p53 activity and vice versa

Carrà, Giovanna; Lingua, Marcello Francesco; Maffeo, Beatrice; Taulli, Riccardo; Morotti, Alessandro

doi:10.1007/s00018-020-03524-9

Cited by 54 publications

(44 citation statements)

References 84 publications

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“…However, unlike PTPN14, which is defined as a tumor suppressor and particularly controls the Hippo signaling pathway (Huang et al, 2013;Liu et al, 2013;Mello et al, 2017;Michaloglou et al, 2013;Wilson et al, 2014), PTPN21 is known to be upregulated in several types of cancer cells and is associated with EGFR activation and intracellular trafficking, implying that this protein might be potentially oncogenic rather than tumor-suppressive (Carlucci et al, 2010;Plani-Lam et al, 2016;Roda-Navarro and Bastiaens, 2014;Wu et al, 2010). While the association between p53 and PTPN21 remains elusive, PTPN21 was reported to inhibit nuclear factor-κB transcriptional activity (Cho et al, 2017), which is known to play a pivotal role in immune responses and be negatively regulated by p53 (Carra et al, 2020;Jang et al, 2020;Pal et al, 2014;Schneider et al, 2010). Therefore, the biological roles and consequences of the HPV E7-PTPN21 interaction in HPV-driven tumorigenesis might differ from those of the HPV E7-PTPN14 interaction and warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18

Lee

Jin

Shin

et al. 2021

Molecules and Cells

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Human papillomaviruses (HPVs) cause cellular hyper proliferationassociated abnormalities including cervical cancer. The HPV genome encodes two major viral oncoproteins, E6 and E7, which recruit various host proteins by direct interaction for proteasomal degradation. Recently, we reported the structure of HPV18 E7 conserved region 3 (CR3) bound to the protein tyrosine phosphatase (PTP) domain of PTPN14, a welldefined tumor suppressor, and found that this intermolecular interaction plays a key role in E7driven transformation and tumorigenesis. In this study, we carried out a molecular analysis of the interaction between CR3 of HPV18 E7 and the PTP domain of PTPN21, a PTP protein that shares high sequence homology with PTPN14 but is putatively oncogenic rather than tumorsuppressive. Through the combined use of biochemical tools, we verified that HPV18 E7 and PTPN21 form a 2:2 complex, with a dissociation constant of 5 nM and a nearly identical binding manner with the HPV18 E7 and PTPN14 complex. Nevertheless, despite the structural similarities, the biological consequences of the E7 interaction were found to differ between the two PTP proteins. Unlike PTPN14, PTPN21 did not appear to be subjected to proteasomal degradation in HPV18positive HeLa cervical cancer cells. Moreover, knockdown of PTPN21 led to retardation of the migration/invasion of HeLa cells and HPV18 E7expressing HaCaT keratinocytes, which reflects its protumor activity. In conclusion, the associations of the viral oncoprotein E7 with PTPN14 and PTPN21 are similar at the molecular level but play different physiological roles.

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Section: Introductionmentioning

confidence: 99%

Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18

Lee

Jin

Shin

et al. 2021

Molecules and Cells

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“…A canonical tumor suppressor, p53, is another target of USP2. Under conditions with cellular stress and/or DNA damage, p53 accumulates in cells and evokes various anti-tumor events such as DNA repair, induction of apoptosis, or cell cycle arrest [27,28]. Loss-of-function of p53 is now believed to be one of the common events underlying tumorigenesis [29].…”

Section: Tumorigenesismentioning

confidence: 99%

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

Kitamura

Hashimoto

2021

IJMS

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Ubiquitin specific protease (USP) 2 is a multifunctional deubiquitinating enzyme. USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A. Other tumorigenic molecules, including epidermal growth factor and fatty acid synthase, are also targets for USP2. USP2 additionally prevents p53 signaling. On the other hand, USP2 functions as a key component of the CLOCK/BMAL1 complex and participates in rhythmic gene expression in the suprachiasmatic nucleus and liver. USP2 variants influence energy metabolism by controlling hepatic gluconeogenesis, hepatic cholesterol uptake, adipose tissue inflammation, and subsequent systemic insulin sensitivity. USP2 also has the potential to promote surface expression of ion channels in renal and intestinal epithelial cells. In addition to modifying the production of cytokines in immune cells, USP2 also modulates the signaling molecules that are involved in cytokine signaling in the target cells. Usp2 knockout mice exhibit changes in locomotion and male fertility, which suggest roles for USP2 in the central nervous system and male genital tract, respectively. In this review, we summarize the cellular events with USP2 contributions and list the signaling molecules that are upstream or downstream of USP2. Additionally, we describe phenotypic differences found in the in vitro and in vivo experimental models.

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“…Moreover, tumor suppressor activity of NF-κB has not been well-documented in human cancers [ 110 ]. Nevertheless, the extensive crosstalk between NF-κB and both wild-type and mutant tumor suppressor p53 indicates that NF-κB may play a role in tumor suppression in humans in certain circumstances [ 111 ].…”

Section: Nf-κb As a Tumor Suppressormentioning

confidence: 99%

NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

Gilmore

2021

Biomedicines

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Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved. These activations can occur due to mutations in the NF-κB transcription factors themselves, in upstream regulators of NF-κB, or in pathways that impact NF-κB. In addition, NF-κB can be activated by tumor-assisting processes such as inflammation, stromal effects, and genetic or epigenetic changes in chromatin. Aberrant NF-κB activity can affect many tumor-associated processes, including cell survival, cell cycle progression, inflammation, metastasis, angiogenesis, and regulatory T cell function. As such, inhibition of NF-κB has often been investigated as an anticancer strategy. Nevertheless, with a few exceptions, NF-κB inhibition has had limited success in human cancer treatment. This review covers general themes that have emerged regarding the biological roles and mechanisms by which NF-κB contributes to human cancers and new thoughts on how NF-κB may be targeted for cancer prognosis or therapy.

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P53 vs NF-κB: the role of nuclear factor-kappa B in the regulation of p53 activity and vice versa

Cited by 54 publications

References 84 publications

Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18

Molecular Analysis of the Interaction between Human PTPN21 and the Oncoprotein E7 from Human Papillomavirus Genotype 18

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

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