Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Cau, Ylenia; Valensin, Daniela; Mori, Mattia; Draghi, Sara; Botta, Maurizio

doi:10.2174/0929867324666170426095015

Cited by 65 publications

(66 citation statements)

References 126 publications

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“…Many of these have been shown to be involved in disease . This fact supports the notion that several 14‐3‐3 protein‐protein interactions (PPIs) can be attractive therapeutic targets …”

Section: Figuresupporting

confidence: 80%

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

et al. 2020

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We report on a stabilizer of the interaction between 14‐3‐3ζ and the Estrogen Receptor alpha (ERα). ERα is a driver in the majority of breast cancers and 14‐3‐3 proteins are negative regulators of this nuclear receptor, making the stabilization of this protein‐protein interaction (PPI) an interesting strategy. The stabilizer (1) consists of three symmetric peptidic arms containing an arginine mimetic, previously described as the GCP motif. 1 stabilizes the 14‐3‐3ζ/ERα interaction synergistically with the natural product Fusicoccin‐A and was thus hypothesized to bind to a different site. This is supported by computational analysis of 1 binding to the binary complex of 14‐3‐3 and an ERα‐derived phosphopeptide. Furthermore, 1 shows selectivity towards 14‐3‐3ζ/ERα interaction over other 14‐3‐3 client‐derived phosphomotifs. These data provide a solid support of a new binding mode for a supramolecular 14‐3‐3ζ/ERα PPI stabilizer.

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Section: Figuresupporting

confidence: 80%

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

et al. 2020

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“…Importantly, it is also known that SRARP interacts with the endogenous 14-3-3 protein (Naderi, 2017). Of note, 14-3-3 is involved in regulating multiple cellular processes and signal transduction pathways by interacting with proteins involved in these processes (Cau et al, 2018;Mhawech, 2005). Therefore, an interaction with 14-3-3 creates another common molecular feature between HSPB7 and SRARP proteins, which may present an underlying mechanism for their function as tumor suppressors.…”

mentioning

confidence: 99%

SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

Naderi

2018

Molecular Oncology

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Deletions of chromosome 1p36 are common in cancers; however, despite extensive studies, there has been limited success for discovering candidate tumor suppressors in this region. SRARP has recently been identified as a novel corepressor of the androgen receptor (AR) and is located on chromosome 1p36. Here, bioinformatics analysis of large tumor datasets was performed to study SRARP and its gene pair, HSPB7. In addition, using cancer cell lines, mechanisms of SRARP and HSPB7 regulation and their molecular functions were investigated. This study demonstrated that SRARP and HSPB7 are a gene pair located 5.2 kb apart on 1p36.13 and are inactivated by deletions and epigenetic silencing in malignancies. Importantly, SRARP and HSPB7 have tumor suppressor functions in clonogenicity and cell viability associated with the downregulation of Akt and ERK. SRARP expression is inversely correlated with genes that promote cell proliferation and signal transduction, which supports its functions as a tumor suppressor. In addition, AR exerts dual regulatory effects on SRARP, and although an increased AR activity suppresses SRARP transcription, a minimum level of AR activity is required to maintain baseline SRARP expression in AR+ cancer cells. Furthermore, as observed with SRARP, HSPB7 interacts with the 14‐3‐3 protein, presenting a shared molecular feature between SRARP and HSPB7. Of note, genome‐ and epigenome‐wide associations of SRARP and HSPB7 with survival strongly support their tumor suppressor functions. In particular, DNA hypermethylation, lower expression, somatic mutations, and lower copy numbers of SRARP are associated with worse cancer outcome. Moreover, DNA hypermethylation and lower expression of SRARP in normal adjacent tissues predict poor survival, suggesting that SRARP inactivation is an early event in carcinogenesis. In summary, SRARP and HSPB7 are tumor suppressors that are commonly inactivated in malignancies. SRARP inactivation is an early event in carcinogenesis that is strongly associated with worse survival, presenting potential translational applications.

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“…The present study specifically focused on the metastatic impact of 14-3-3ζ in relatively early stages of resectable lung adenocarcinoma without distant metastasis, which is unlike the majority of the previous studies performed in lung cancer, which included a number of pathologies and advanced stage cancers (46,47). 14-3-3ζ overexpression exerts complex biological effects via its interaction with a number of different proteins in a spatial and a temporal fashion, emphasizing individual functions in diverse signaling pathways in various tumor types (48,49). In addition, 14-3-3ζ exhibits multiple, opposing roles, making the analysis of its effects in complex systems challenging.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of 14‑3‑3ζ in lung tissue predicts an improved outcome in patients with lung adenocarcinoma

Liu

et al. 2018

Oncol Lett

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One of the factors limiting the survival rate of patients with lung cancer is the high risk for recurrence following surgical resection. Previous studies indicate that 14-3-3ζ is a central cellular hub protein that regulates multiple signaling pathways involved in cancer progression. The present study evaluated the prognostic significance of 14-3-3ζ in patients with lung adenocarcinoma. The expression of 14-3-3ζ and E-cadherin, an important protein involved in the epithelial-mesenchymal transition, was evaluated by immunohistochemistry in lung tumor tissues and adjacent normal lung tissues resected from 123 patients with lung adenocarcinoma. The correlation between the two proteins, their association with clinicopathological features and their prognostic significance were subsequently analyzed. Within these parameters, an overall survival (OS) prediction model was constructed using multivariate Cox proportional hazards regression. The expression of 14-3-3ζ was upregulated in lung adenocarcinoma, in contrast to E-cadherin, which was downregulated in lung adenocarcinoma tissues compared with normal tissues. In addition, the expression of 14-3-3ζ was positively correlated with that of E-cadherin (r=0.256, P=0.012) and differentiation (P<0.001). Increased E-cadherin expression was indicative of smaller tumor size and greater differentiation, and the overexpression of 14-3-3ζ and E-cadherin were associated with longer OS (P=0.010 and P=0.006, respectively). Finally, a multivariate analysis revealed that TNM stage and 14-3-3ζ were independent prognostic indicators (P<0.001 and P=0.026, respectively). 14-3-3ζ may function as a tumor suppressor associated with E-cadherin upregulation and could be used as a prognostic biomarker for resected lung adenocarcinoma. These findings provide a novel insight on potential intervention strategies for patients with lung cancer.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Cited by 65 publications

References 126 publications

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

Overexpression of 14‑3‑3ζ in lung tissue predicts an improved outcome in patients with lung adenocarcinoma

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