Dataset Information

Dephosphorylation of nucleophosmin by PP1? facilitates pRB binding and consequent E2F1-dependent DNA repair.

ABSTRACT: Nucleophosmin (NPM) is an important phosphoprotein with pleiotropic functions in various cellular processes. Although phosphorylation has been postulated as an important functional determinant, possible regulatory roles of this modification on NPM are not fully characterized. Here, we find that NPM is dephosphorylated on various threonine residues (Thr199 and Thr234/237) in response to UV-induced DNA damage. Further experiments indicate that the serine/threonine protein phosphatase PP1? is a physiological NPM phosphatase under both the genotoxic stress and growth conditions. As a consequence, NPM in its hypophosphorylated state facilitates DNA repair. Finally, our results suggest that one possible mechanism of this protective response lies in enhanced NPM-retinoblastoma tumor suppressor protein (pRB) interaction, leading to the relief of the repressive pRB-E2F1 circuitry and the consequent transcriptional activation of E2F1 and several downstream DNA repair genes. Thus, this study unveils a key phosphatase of NPM and highlights a novel mechanism by which the PP1?-NPM pathway contributes to cellular DNA damage response.

SUBMITTER: Lin CY

PROVIDER: S-EPMC3002393 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Dephosphorylation of nucleophosmin by PP1β facilitates pRB binding and consequent E2F1-dependent DNA repair.

Lin Chiao Yun CY Tan Bertrand Chin-Ming BC Liu Hsuan H Shih Chii-Jiun CJ Chien Kun-Yi KY Lin Chih-Li CL Yung Benjamin Yat-Ming BY

Molecular biology of the cell 20101020 24

Nucleophosmin (NPM) is an important phosphoprotein with pleiotropic functions in various cellular processes. Although phosphorylation has been postulated as an important functional determinant, possible regulatory roles of this modification on NPM are not fully characterized. Here, we find that NPM is dephosphorylated on various threonine residues (Thr199 and Thr234/237) in response to UV-induced DNA damage. Further experiments indicate that the serine/threonine protein phosphatase PP1β is a phy ...[more]

PMID: 20962268

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Project description:Here we report that ALDH1L1 (FDH, a folate enzyme with tumor suppressor-like properties) inhibits cell motility. The underlying mechanism involves F-actin stabilization, re-distribution of cytoplasmic actin toward strong preponderance of filamentous actin and formation of actin stress fibers. A549 cells expressing FDH showed a much slower recovery of green fluorescent protein-actin fluorescence in a fluorescence recovery after photobleaching assay, as well as an increase in G-actin polymerization and a decrease in F-actin depolymerization rates in pyren-actin fluorescence assays indicating the inhibition of actin dynamics. These effects were associated with robust dephosphorylation of the actin depolymerizing factor cofilin by PP1 and PP2A serine/threonine protein phosphatases, but not the cofilin-specific phosphatases slingshot and chronophin. In fact, the PP1/PP2A inhibitor calyculin prevented cofilin dephosphorylation and restored motility. Inhibition of FDH-induced apoptosis by the Jun N-terminal kinase inhibitor SP600125 or the pan-caspase inhibitor zVAD-fmk did not restore motility or levels of phosphor-cofilin, indicating that the observed effects are independent of FDH function in apoptosis. Interestingly, cofilin small interfering RNA or expression of phosphorylation-deficient S3A cofilin mutant resulted in a decrease of G-actin and the actin stress fiber formation, the effects seen upon FDH expression. In contrast, the expression of S3D mutant, mimicking constitutive phosphorylation, prevented these effects further supporting the cofilin-dependent mechanism. Dephosphorylation of cofilin and inhibition of motility in response to FDH can also be prevented by the increased folate in media. Furthermore, folate depletion itself, in the absence of FDH, resulted in cofilin dephosphorylation and inhibition of motility in several cell lines. Our experiments showed that these effects were folate specific and not a general response to nutrient starvation. Overall, this study shows the presence of distinct intracellular signaling pathways regulating motility in response to folate status and points toward mechanisms involving folates in promoting a malignant phenotype.

Dataset Information

Dephosphorylation of nucleophosmin by PP1? facilitates pRB binding and consequent E2F1-dependent DNA repair.

Publications

Dephosphorylation of nucleophosmin by PP1β facilitates pRB binding and consequent E2F1-dependent DNA repair.

Similar Datasets

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