Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1) by aurora kinase B is critical for mitotic progression

Shandilya, Jayasha; Senapati, Parijat; Dhanasekaran, Karthigeyan; Bangalore, Suma S.; Kumar, Manoj; Kishore, A. Hari; Bhat, Akshay; Kodaganur, Gopinath S.; Kundu, Tapas K.

doi:10.1016/j.febslet.2014.05.014

Cited by 21 publications

(11 citation statements)

References 25 publications

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“…CK2 is thought to maintain the basal phosphorylated state of PC4 during interphase, but the kinase responsible for PC4 phosphoenrichment (hyperphosphorylation) during mitosis was not known. A similar situation was observed with NPM1 until it was found to be a target of Aurora kinase A and B during the cell cycle [16,18]. Our studies revealed that the phosphorylation of PC4 by Aurora kinase had important functional consequences for mitosis.…”

Section: Discussionsupporting

confidence: 83%

Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes

et al. 2016

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Positive coactivator 4 (PC4), a human transcriptional coactivator, is involved in diverse processes like chromatin organization and transcription regulation. It is hyperphosphorylated during mitosis, with unknown significance. For the first time, we demonstrate the function of PC4 outside the nucleus upon nuclear envelope breakdown. A fraction of PC4 associates with Aurora A and Aurora B and undergoes phosphorylation, following which PC4 activates both Aurora A and B to sustain optimal kinase activity to maintain the phosphorylation gradient for the proper functioning of the mitotic machinery. This mitotic role is evident in PC4 knockdown cells where the defects are rescued only by the catalytically active Aurora kinases, but not the kinase-dead mutants. Similarly, the PC4 phosphodeficient mutant failed to rescue such defects. Hence, our observations establish a novel mitotic function of PC4 that might be dependent on Aurora kinase-mediated phosphorylation.

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Section: Discussionsupporting

confidence: 83%

Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes

et al. 2016

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“…Notably, CIGB-300 has been subjected to several phase I clinical trials and has entered phase II [151,152]. Interestingly, CIGB-300 was shown to bind NPM1 and to inhibit CK2-mediated phosphorylation of NPM1 at Ser125 inducing damage to the nucleolar architecture and massive apoptosis [149], in line with the putative implication of NPM1 phospho-Ser125 in the maintenance of the nucleolar assembly, in ribosome biogenesis, and in cytokinesis [153][154][155].…”

Section: Synthetic Compoundsmentioning

confidence: 90%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

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“…The NPM1 protein is a nuclear chaperone that can be converted in the nucleus and cytoplasm, and has various types of biological functions, including gene stability, DNA repairs, tumorigenesis, etc. . Studies have shown that NPM1 protein can regulate the localization, aggregation and stability of P53 and p14 ARF proteins, thereby playing an important role in tumorigenesis .…”

Section: Discussionmentioning

confidence: 99%

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

Fan

Wen

et al. 2017

APMIS

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To analyze the expression trends and clinical significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1/Ref-1) and Nucleophosmin (NPM1) proteins in high-grade serous ovarian adenocarcinoma (HGSC). The expressions of APE1/Ref-1 and NPM1 proteins in 94 patients with HGSC were determined using the immunohistochemical (IHC) method, and their relationships with clinicopathological features were analyzed by the χ test or Fisher's exact test. The follow-up data, Cox proportional hazards univariate and multivariate survival analyses were integrated to evaluate the prognostic factors affecting patients with HGSC. In the normal fallopian tubes, APE1/Ref-1 and NPM1 protein were mainly distributed in the nuclear. The HGSC experienced changes in the cellular localization of APE1/Ref-1 and NPM1 protein expressions, which were abnormally expressed in the cytoplasm. The rates of abnormal cytoplasmic expression of APE1/Ref-1 and NPM1 proteins in 94 patients with HGSC were 69.1% and 73.4%, respectively, which were significantly higher than the normal fallopian tube tissues (p < 0.05). The abnormal cytoplasmic APE1/Ref-1 and NPM1 are significantly correlated with the lymph node metastasis, chemosensitivity, FIGO staging, and prognosis. The COX multivariate survival analysis showed that the abnormal expression of APE1/Ref-1 protein, FIGO staging, and lymph node metastasis are independent prognostic factors. Collectively, the abnormal cytoplasmic APE1/Ref-1 and NPM1 proteins are associated with the oncogenic progression and chemoresistance of HGSC, and predict a poor prognosis.

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Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1) by aurora kinase B is critical for mitotic progression

Cited by 21 publications

References 25 publications

Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes

Multifunctional human transcriptional coactivator protein PC4 is a substrate of Aurora kinases and activates the Aurora enzymes

Nucleophosmin in Its Interaction with Ligands

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

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