Nup62‐mediated nuclear import of p63 in squamous cell carcinoma

Borlido, Joana; D’Angelo, Maximiliano A.

doi:10.15252/embr.201745497

Cited by 9 publications

(7 citation statements)

References 10 publications

(22 reference statements)

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“…Of course, we cannot completely rule out the fact that some of the Kaps might translocate through phosphorylated NPCs at longer simulation times. Nevertheless, the trend of a reduced probability for active transport through phosphorylated pores and an increased probability for passive transport upon phosphorylation is in accordance with experimental observations [27,29,30,31,32].…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, there is evidence which confirms that FG-Nups undergo phosphorylation in vivo as well [21,23,27,28]. Transport studies demonstrated that the phosphorylation of nucleoporins results in decreased kinetics of active transport of Kap95 [25,27,29] and Kap-cargo complexes [30,31], and increased kinetics of passive transport [32]. These studies indicate that phosphorylation can modulate the selective permeability of the NPCs.…”

Section: Introductionmentioning

confidence: 92%

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The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study

Mishra

Sipma

Veenhoff

et al. 2019

IJMS

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Nuclear pore complexes (NPCs) are large protein complexes embedded in the nuclear envelope separating the cytoplasm from the nucleoplasm in eukaryotic cells. They function as selective gates for the transport of molecules in and out of the nucleus. The inner wall of the NPC is coated with intrinsically disordered proteins rich in phenylalanine-glycine repeats (FG-repeats), which are responsible for the intriguing selectivity of NPCs. The phosphorylation state of the FG-Nups is controlled by kinases and phosphatases. In the current study, we extended our one-bead-per-amino-acid (1BPA) model for intrinsically disordered proteins to account for phosphorylation. With this, we performed molecular dynamics simulations to probe the effect of phosphorylation on the Stokes radius of isolated FG-Nups, and on the structure and transport properties of the NPC. Our results indicate that phosphorylation causes a reduced attraction between the residues, leading to an extension of the FG-Nups and the formation of a significantly less dense FG-network inside the NPC. Furthermore, our simulations show that upon phosphorylation, the transport rate of inert molecules increases, while that of nuclear transport receptors decreases, which can be rationalized in terms of modified hydrophobic, electrostatic, and steric interactions. Altogether, our models provide a molecular framework to explain how extensive phosphorylation of FG-Nups decreases the selectivity of the NPC.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 92%

The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study

Mishra

Sipma

Veenhoff

et al. 2019

IJMS

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“…In upper vertebrates, the ZEB family includes two proteins, ZEB1 and ZEB2, which act as either transcriptional repressors or activators depending on the target gene and tissue. 60 [74][75][76][77][78] Indeed, altered ΔNp63 expression is also present in oral epithelial dysplasia, playing a potential role in malignant transformation of epithelial cells. 79,80 4.5 | Additional transcription factors E12 and E47, encoded by the E2A gene, belong to the same transcription factor family of Twist proteins.…”

Section: Zeb Familymentioning

confidence: 99%

Epithelial‐to‐mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities

Ling

Cheng

Tao

2020

Intl Journal of Cancer

147

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Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms of oral cancer worldwide. Although great efforts have been made in the past decades, the 5‐year survival rate of OSCC patients is no more than 60% due to tumor metastasis and subsequent recurrence. The metastasis from the primary site is due to a complex process known as epithelial‐to‐mesenchymal transition (EMT). During the EMT, epithelial cells gradually acquire the structural and functional characteristics of mesenchymal cells, leading to the upregulation of cell migration and the promotion of tumor cell dissemination. Therefore, EMT attracted broad attention due to its close relationship with cancer invasion and metastasis. Therefore, in the present review, an extensive description of the current research on OSCC and the role of EMT in this cancer type is provided, including diverse EMT markers, regulatory networks and crucial EMT‐inducing transcription factors in OSCC. Moreover, a brief summary was made regarding the current application of EMT‐correlated indexes in the prognostic analysis of OSCC patients, and the potential therapeutic approaches against OSCC and difficulties in the development of an effective anti‐EMT treatment are discussed. Our aim is to provide novel insights to develop new strategies to combat OSCC by targeting EMT.

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“…While not covered exhaustively in this review, mechanisms including, but not limited to, stabilization, degradation, and cellular localization are involved in modulating ΔNp63α activity (reviewed in [45]). Recently described examples of additional mechanisms include interactions with syntaxin-binding protein 4 to suppress the proteolysis of ΔNp63α, leading to decreased turnover [46,47], and increased activity of the nucleoporin NUP62 to facilitate ΔNp63α nuclear import, potentiating its role as a transcription factor [48,49]. Differential methylation status of the ΔNp63α gene locus is also involved in driving its expression [26].…”

Section: Mechanisms Of Transcriptional Regulation By P63mentioning

confidence: 99%

Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

Moses

George

Sakakibara

et al. 2019

IJMS

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The p63 gene is a member of the p53/p63/p73 family of transcription factors and plays a critical role in development and homeostasis of squamous epithelium. p63 is transcribed as multiple isoforms; ΔNp63α, the predominant p63 isoform in stratified squamous epithelium, is localized to the basal cells and is overexpressed in squamous cell cancers of multiple organ sites, including skin, head and neck, and lung. Further, p63 is considered a stem cell marker, and within the epidermis, ΔNp63α directs lineage commitment. ΔNp63α has been implicated in numerous processes of skin biology that impact normal epidermal homeostasis and can contribute to squamous cancer pathogenesis by supporting proliferation and survival with roles in blocking terminal differentiation, apoptosis, and senescence, and influencing adhesion and migration. ΔNp63α overexpression may also influence the tissue microenvironment through remodeling of the extracellular matrix and vasculature, as well as by enhancing cytokine and chemokine secretion to recruit pro-inflammatory infiltrate. This review focuses on the role of ΔNp63α in normal epidermal biology and how dysregulation can contribute to cutaneous squamous cancer development, drawing from knowledge also gained by squamous cancers from other organ sites that share p63 overexpression as a defining feature.

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Nup62‐mediated nuclear import of p63 in squamous cell carcinoma

Cited by 9 publications

References 10 publications

The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study

The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study

Epithelial‐to‐mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities

Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

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