The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy

Chu, Isabel; Hengst, Ludger; Slingerland, Joyce M.

doi:10.1038/nrc2347

Cited by 890 publications

(1,061 citation statements)

References 184 publications

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“…Moreover, AKT can phosphorylate p27 on Thr157, thus delaying its nuclear import (Liang et al, 2002) and facilitating its cytoplasmic sequestration into complexes with cyclin D-CDKs (Chu et al, 2008), whereas AKT inhibition leads to p27 accumulation and nuclear localization (Motti et al, 2005;Yang et al, 2006). This mechanism seems to function also in MM cell lines in which phospho-AKT inhibition mediated by the PI3 kinase inhibitor LY294002 induces an increase in p27 levels Mikami et al, 2010) and in its nuclear/cytoplasmic ratio (Supplementary Figure S2).…”

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 96%

“…p27 has a crucial role in cell cycle control, mainly acting as a negative regulator of the G 1 -S transition by binding and inhibiting the cyclin E-CDK2 complex. Although this tumorsuppressive function of p27 is the best-characterized, p27 behaves as an atypical tumor suppressor and a regulator of key cellular processes, such as proliferation, motility and apoptosis, in both a positive and a negative manner depending on its subcellular localization (Chu et al, 2008).…”

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 99%

“…Moreover, the cytoplasmic sequestration of p27 into complexes with cyclin D-CDK4/6 can contribute to cell cycle progression also by relieving cyclin E-CDK2 from p27 constraint (Sherr and Roberts, 1999). Furthermore, cytoplasmic mislocalization of p27 seems to contribute to progression of many cancers also by increasing cell motility and metastasis and, importantly, inhibiting apoptosis (Blagosklonny, 2002;Coqueret, 2003;Wang et al, 2005;Chu et al, 2008). Therefore, p27 has been defined as a nuclear tumor suppressor and a cytoplasmic oncogene.…”

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 99%

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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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Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 96%

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 99%

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 99%

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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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“…Loss of expression of p27kip1 has been described as a frequent event in several human cancers 16 conferring a proliferative advantage that can lead to tumour formation. This behaviour suggests p27 may function as a tumour suppressor, although it is rarely mutated in cancer 17, 18.…”

Section: Introductionmentioning

confidence: 99%

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

Capasso

McDaniel

Cimmino

et al. 2017

J Cellular Molecular Medi

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The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP‐2, both transfected with pGL3‐CDKN1B‐CC or pGL3‐CDKN1B‐TT constructs. We identified an association of the rs34330 T allele (‐79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying ‐79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility.

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“…p21 Cip1 or p27 Kip1 inactivation may also occur through epigenetic alterations, increased proteolysis or as a consequence of defective p53 signaling. 2,6,[27][28][29] The involvement of Ink4, Cip1 and Kip1 proteins in tumor development has been evaluated in vivo using different genetic mouse models. Genetic ablation of p21 Cip1 results in altered response to DNA damage responses and increased tumor susceptibility, specifically in mesenchymal and hematopoietic cells, at advanced age.…”

Section: Discussionmentioning

confidence: 99%

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

Quereda

Porlan

Cañamero³

et al. 2015

Cell Death Differ

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Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21 Cip1 and p27 Kip1 proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21 Cip1 and p27 Kip1 in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.

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The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy

Cited by 890 publications

References 184 publications

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

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

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

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