Identification of a putative nuclear localization signal in the tumor suppressor maspin sheds light on its nuclear import regulation

Reina, Jeffrey; Zhou, Lixin; Fontes, M.R.M.; Panté, Nelly; Cella, Nathalie

doi:10.1002/2211-5463.12626

Cited by 12 publications

(24 citation statements)

References 46 publications

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“…26 Furthermore, Reina et al reported that the transport of maspin from the cytoplasm to the nucleus involves a 28-amino acid sequence within the maspin protein and three-dimensional regulation of protein structure. 27 These findings may help explain our observations, which indicated that the mechanism regulating the subcellular localization of maspin is disrupted in RERF-LC-KJ cells. However, since the detailed molecular mechanisms of nuclear translocation of maspin have not yet been elucidated, further investigations are required to clarify this finding.…”

Section: Discussionsupporting

confidence: 69%

Investigation of the Subcellular Localization-Dependent Anti- or Pro-Tumor Functions of Maspin in Human Lung Adenocarcinoma Cell Line

2022

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Background Mammary serine protease inhibitor (maspin) is well known as a tumor suppressor gene in several types of cancers and its nuclear localization is essential for its tumor-suppressive function. We previously reported that the cytoplasmic-only localization of maspin is significantly correlated with unfavorable prognosis in patients with lung adenocarcinoma (LUAD). To clarify whether maspin in LUAD acts as a tumor promoter or suppressor, we examined the subcellular localization-dependent biological functions of maspin in human LUAD cell lines. Methods The expression levels and subcellular localization of maspin were investigated by performing immunoblotting and immunofluorescence in human LUAD cell lines (PC-9, A549, NCI-H23, RERF-LC-KJ) and human bronchial epithelial cell line (BEAS-2B). We then established stable cell lines overexpressing maspin (A549-maspin and RERF-LC-KJ-maspin) and investigated their subcellular localization. Cell invasion assays of these cell lines were performed to examine their invasiveness. Moreover, the mRNA expression levels between epithelial cell markers (E-cadherin) and mesenchymal cell markers (N-cadherin and vimentin) were compared. Results The expression of maspin in PC-9 cells was comparable to that in BEAS-2B cells, whereas its expression in A549, NCI-H23, and RERF-LC-KJ cells was decreased. The cell invasion capability of A549-maspin cells showing pancellular expression was significantly decreased compared with that of A549-control cells. By contrast, the cell invasion capability of RERF-LC-KJmaspin cells showing cytoplasmic-only expression was significantly increased compared with that of RERF-LC-KJ-control cells. The mRNA expression levels of N-cadherin, but not E-cadherin and vimentin, in A549maspin cells was significantly downregulated compared with that in A549-control cells. No significant differences in these markers were observed between RERF-LC-KJ-maspin and RERF-LC-KJ-control cells. Conclusion The invasive capability of LUAD cells is regulated by the intracellular localization of maspin. Clarification of the molecular mechanism underlying the subcellular localization-dependent function of maspin will promote a deeper understanding of LUAD development and progression.

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Section: Discussionsupporting

confidence: 69%

Investigation of the Subcellular Localization-Dependent Anti- or Pro-Tumor Functions of Maspin in Human Lung Adenocarcinoma Cell Line

2022

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“…Alternatively, Reina et al . reported that the sequence of 28 amino acids in maspin protein (KLIKRLYVDKSLNLSTEFI-SSTKRPYAK) acts as a NLS and speculated that the nuclear-cytoplasmic transport of maspin may be controlled through the regulation of its three-dimensional conformation 43 . Although these reports help us in understanding the mechanisms underlying subcellular translocation of maspin, the exact details of this process remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Role of cytoplasmic localization of maspin in promoting cell invasion in breast cancer with aggressive phenotype

Sakabe

Wakahara

Shiota

et al. 2021

Sci Rep

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Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is downregulated during carcinogenesis and breast cancer progression. While the nuclear localization of maspin is essential for tumor suppression, we previously reported that the cytoplasmic localization of maspin was significantly correlated with poor prognosis in breast cancer patients. To understand the mechanisms that underlie oncogenic role of cytoplasmic maspin, we studied its biological function in breast cancer cell lines. Subcellular localization of maspin in MDA-MB-231 breast cancer cells was mainly detected in the cytoplasm, whereas in MCF10A mammary epithelial cells, maspin was present in both cytoplasm and nucleus. In MDA-MB-231 cells, maspin overexpression promoted cell proliferation and cell invasion, whereas maspin downregulation resulted in the opposite effect. Further, we observed that SRGN protein levels were increased in MDA-MB-231 cells stably overexpressing maspin. Finally, maspin overexpression in MDA-MB-231 cells resulted in the N-cadherin and epithelial mesenchymal transition (EMT)-related transcription factors upregulation, and TGFβ signaling pathway activation. These results suggested that cytoplasmic maspin enhances the invasive and metastatic potential in breast cancer cells with aggressive phenotype by inducing EMT via SRGN/TGFβ axis. This study demonstrated a novel biological function of cytoplasmic maspin in progression of breast cancer cells with an aggressive phenotype.

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“…Recently, maspin residues from 87-114 were proposed to harbor nuclear localization signal, and their exposure impact maspin localization (Reina et al ., 2019). When the exposure has been calculated for the entire length, maspin-S176 showed slightly higher solvent accessibility than maspin-P176, however, for 87-94 (s2A), maspin-S176 was significantly higher referring to the higher possibility of this variant being nuclear-localized (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

P176S polymorphism in Maspin rewires electrostatic interaction that alters Maspin functionality

Anwar

Haseeb

Choi

et al. 2022

Preprint

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Maspin has been known to regress tumors by inhibiting angiogenesis, however, its roles have been reported to be context and sequence-dependent. There are various proteins and cofactors that bind with maspin possibly explaining the conflicting roles of maspin. Moreover, maspin polymorphic forms have also been linked to tumor regression or survival, for instance, maspin with Ser at 176 (maspin-S176) promotes tumor while maspin with Pro at 176 (maspin-Pro176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamic simulation, a possible link between polymorphic forms and tumor progression has been established. First, the maspin is dynamically stable with either amino acid at 176 position, secondly, differential contacts have been observed among various regions, thirdly, these contacts have significantly altered the electrostatic energetics of various residues, and finally, these altered electrostatics of maspin-S176 and maspin-P176 rewired the polar contacts that abolished the allosteric control in protein. By combining these factors, the altered electrostatics can substantially affect the localization, and the preference of maspin binding partners, thus, culminating in a different maspin-protein (cofactor)-interaction landscape that could have been manifested with conflicting reports in previous studies. Here, the underlying reason has been highlighted and discussed that could be helpful for better therapeutic manipulations.

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Identification of a putative nuclear localization signal in the tumor suppressor maspin sheds light on its nuclear import regulation

Cited by 12 publications

References 46 publications

Investigation of the Subcellular Localization-Dependent Anti- or Pro-Tumor Functions of Maspin in Human Lung Adenocarcinoma Cell Line

Investigation of the Subcellular Localization-Dependent Anti- or Pro-Tumor Functions of Maspin in Human Lung Adenocarcinoma Cell Line

Role of cytoplasmic localization of maspin in promoting cell invasion in breast cancer with aggressive phenotype

P176S polymorphism in Maspin rewires electrostatic interaction that alters Maspin functionality

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