Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer

Chiappetta, Gennaro; Marco, Carmela De; Quintiero, Alfina; Califano, Daniela; Gherardi, Simona; Malanga, Donatella; Scrima, Marianna; Montero‐Conde, Cristina; Cito, Letizia; Monaco, Mario; Motti, Maria Letizia; Pasquinelli, Rosa; Agosti, Valter; Robledo, Mercedes; Viglietto, Giuseppe

doi:10.1677/erc-06-0030

Cited by 34 publications

(29 citation statements)

References 56 publications

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“…SKP2 was inversely associated with p27Kip1 protein levels (40). We therefore determined the role of both SKP2 and p27Kip1 as prognostic markers and found that those CRC that exhibit deregulation of SKP2 and p27Kip1, i.e., high level of SKP2 and low level of p27Kip1, have decreased overall survival.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer

Uddin¹,

Ahmed²,

Bavi³

et al. 2008

Cancer Research

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S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. We investigated the role of SKP2 and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and the NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. A colorectal cancer (CRC) subset with high level of SKP2 and low level of p27Kip1 showed a decreased overall survival (P = 0.0057). Treatment of CRC cell lines with bortezomib or expression of small interfering RNA of SKP2 causes down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of CRC cells with bortezomib causes apoptosis by involving the mitochondrial pathway and activation of caspases. In addition, treatment of CRC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Finally, treatment of CRC cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice via down-regulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of CRC. [Cancer Res 2008;68(9):3379-88]

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Section: Discussionmentioning

confidence: 99%

Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer

Uddin¹,

Ahmed²,

Bavi³

et al. 2008

Cancer Research

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“…MSTO-211H, REN and MET-5A cells were stably transduced with lentiviral vectors expressing a set of five short hairpin RNAs (shRNAs) against CDKN1B transcript (Mission shRNA, Sigma-Aldrich) and the non-target control (Mission non-target control, Sigma-Aldrich). Lentiviral vector preparation and infection was performed as previously described (Chiappetta et al, 2007). The effect of SRC inhibition on cell viability and caspase-3 activity was evaluated in MSTO-211H, REN and MET-5A cells expressing p27 and not expressing p27 after treatment of these cell lines with 7.5 mM SI83 and SI91 for 72 h. Before performing caspase-3 assay, cells were counted with trypan blue and the obtained data were used to evaluate cell viability.…”

Section: Conflict Of Interestmentioning

confidence: 99%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo [3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclindependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a wellestablished adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.

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“…Therefore, alternative mechanisms that act at the posttranscriptional or post-translational level have been suggested. These alternative mechanisms include a lower translation rate of CDKN1B mRNA (19), an increase in protein degradation (20,21), and the cytosolic mislocalization of p27 protein (22,23,24).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

Malanga¹,

Gisi²,

Riccardi³

et al. 2012

European Journal of Endocrinology

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Objective: The aim of this study was to investigate the presence of germline mutations in the CDKN1B gene that encodes the cyclin-dependent kinase (Cdk) inhibitor p27 in multiple endocrine neoplasia 1 (MEN1)-like Spanish index patients. The CDKN1B gene has recently been identified as a tumor susceptibility gene for MEN4, with six germline mutations reported so far in patients with a MEN-like phenotype but negative for MEN1 mutations. Design and methods: Fifteen Spanish index cases with MEN-like symptoms were screened for mutations in the CDKN1B gene and the mutant variant was studied functionally by transcription/translation assays in vitro and in transiently transfected HeLa cells. Results: We report the identification of a heterozygous GAGA deletion in the 5 0 -UTR of CDKN1B, NM_004064.3:c.-32_-29del, in a patient affected by gastric carcinoid tumor and hyperparathyroidism. This deletion falls inside the region that is responsible for CDKN1B transcription and is predicted to destroy a secondary stem and loop structure that includes the GAGAGA element responsible for ribosome recruitment. Accordingly, in vitro studies of coupled transcription/translation assays and transient transfection in HeLa cells showed that the GAGA deletion in the CDKN1B 5 0 -UTR significantly impairs the transcription of downstream reporter luciferase (of w40-60%) and, possibly, the translation of the corresponding mRNA. This mutation was associated with a significant reduction in the amount of CDKN1B mRNA in peripheral blood leukocytes from the patient, as demonstrated by quantitative real-time PCR. Conclusions: Our results confirm that germline CDKN1B mutations may predispose to a human MEN4 condition and add novel evidence that alteration in the transcription/translation rate of CDKN1B mRNA might be the mechanism implicated in tumor susceptibility.

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Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer

Cited by 34 publications

References 56 publications

Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer

Bortezomib (Velcade) Induces p27Kip1 Expression through S-Phase Kinase Protein 2 Degradation in Colorectal Cancer

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

Functional characterization of a rare germline mutation in the gene encoding the cyclin-dependent kinase inhibitor p27Kip1 (CDKN1B) in a Spanish patient with multiple endocrine neoplasia-like phenotype

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