p27 Kip1 signaling: Transcriptional and post-translational regulation

Hnit, Su Su Thae; Xie, Chanlu; Mu, Yuguang; Holst, Jeff; Bensoussan, Alan; Souza, Paul de; Zhong, Li; Dong, Qihan

doi:10.1016/j.biocel.2015.08.005

Cited by 86 publications

(101 citation statements)

References 41 publications

(92 reference statements)

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“…We therefore evaluated whether TRMP could regulate the half-life of p27. Consistent with the previous reports 42 , p27 was revealed as a labile protein with a half-life of approximately 2 h. Nevertheless, the half-life of p27 was not affected by either knockdown or ectopic expression of TRMP in both A549 and U2OS cells (Fig. 4e–h, Supplementary Figures S3I–S3L), indicating that TRMP does not interfere with p27 protein turnover.…”

Section: Resultssupporting

confidence: 91%

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TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

et al. 2018

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The tumor suppressor p53 plays a pivotal role in the protection against cancer. Increasing evidence suggests that long noncoding RNA (lncRNA) plays an important role in the regulation of the p53 pathway, however, the detailed mechanisms remain to be further elucidated. In this study, we report a new p53-inducible lncRNA that we termed TRMP (TP53-regulated modulator of p27). As a direct transcriptional target of p53, TRMP plays an unexpected pro-survival function. Knockdown of TRMP inhibits cell proliferation by inducing a G1 cell cycle arrest. Mechanistically, TRMP suppresses internal ribosomal entry site (IRES)-dependent translation of p27 by competing p27 mRNA for polypyrimidine tract-binding protein 1 (PTBP1) binding. Furthermore, TRMP is able to regulate cell proliferation, G1/S cell cycle progression, and tumor xenograft growth via the inhibition of p27. Taken together, these findings suggest lncRNA as a new layer to fine-tune the p53 response and reveal TRMP as an important downstream effector of p53 activity.

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Section: Resultssupporting

confidence: 91%

“…We next determined how TRMP regulates p27 protein levels. It has been previously shown that p27 protein undergoes rapid turnover via the ubiquitin–proteasome-dependent degradation pathway 42 . We therefore evaluated whether TRMP could regulate the half-life of p27.…”

Section: Resultsmentioning

confidence: 99%

TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

et al. 2018

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“…The reason for this discrepancy remains unclear, but could be rather attributed to a complex regulation of p27 translation and turnover. 69,70 In fact, the decreased levels of all three studied proteins as well as eIF3A were also observed in some experiments with HeLa cells, which could be explained by a drop in total translation efficiency below a critical level due to more efficient ABCE1 depletion. In summary, our initial results suggest that ABCE1 may not be specifically required for the translation of eIF3A-regulated proteins, although more potential targets must be further analyzed for a comprehensive conclusion.…”

Section: Abce1 Downregulation Impairs Cell Proliferation and Cell Cycmentioning

confidence: 76%

ABCE1 is essential for S phase progression in human cells

et al. 2016

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ABCE1 is a highly conserved protein universally present in eukaryotes and archaea, which is crucial for the viability of different organisms. First identified as RNase L inhibitor, ABCE1 is currently recognized as an essential translation factor involved in several stages of eukaryotic translation and ribosome biogenesis. The nature of vital functions of ABCE1, however, remains unexplained. Here, we study the role of ABCE1 in human cell proliferation and its possible connection to translation. We show that ABCE1 depletion by siRNA results in a decreased rate of cell growth due to accumulation of cells in S phase, which is accompanied by inefficient DNA synthesis and reduced histone mRNA and protein levels. We infer that in addition to the role in general translation, ABCE1 is involved in histone biosynthesis and DNA replication and therefore is essential for normal S phase progression. In addition, we analyze whether ABCE1 is implicated in transcript-specific translation via its association with the eIF3 complex subunits known to control the synthesis of cell proliferation-related proteins. The expression levels of a few such targets regulated by eIF3A, however, were not consistently affected by ABCE1 depletion.

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“…31 In early G1, phosphorylation of p27Kip1 at Ser10 by AKT facilitates its binding to chromosomal maintenance 1 (CRM1) and its transport from the nucleus to the cytoplasm. 32 Furthermore, in the early G1 phase, p27Kip1 phosphorylation at Thr157 and Thr198 by AKT causes a delay in nuclear import. 33 MYC can also suppress p27Kip1 expression through several pathways.…”

Section: Mt Enhances the Antitumor Effect Of Sorafenib Via G0/g1 Phasmentioning

confidence: 99%

“…33 MYC can also suppress p27Kip1 expression through several pathways. 32 Thus, we examined the expression of p27, c-myc and AKT.…”

Section: Mt Enhances the Antitumor Effect Of Sorafenib Via G0/g1 Phasmentioning

confidence: 99%

Melatonin enhances the anti-tumor effect of sorafenib via AKT/p27-mediated cell cycle arrest in hepatocarcinoma cell lines

et al. 2017

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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, often diagnosed in late stages when most therapeutic methods are not very effective. The introduction of the multikinase inhibitor sorafenib as the standard of care has opened a window of hope for patients with advanced HCC, patients with very poor prognosis; however, patients usually develop acquired resistance to sorafenib limiting its therapeutic benefits. Melatonin (MT), an indoleamine compound produced in the pineal gland, has shown a substantial beneficial effect in increasing the efficacy of common anticancer drugs and decreasing their toxic effects. Here we demonstrate that MT potentiated the sorafenib-mediated inhibition of cell viability and colony formation in HCC cell lines. Moreover, combined treatment of MT and sorafenib enhanced the cell cycle arrest of HCC cells at the G0/G1 phase. Co-treatment of sorafenib and MT was found to upregulate p27, an inhibitor of several cyclin-dependent kinases (CDK), and downregulate p-AKT, c-myc, cyclin D1 and CDK4/6 protein expression. Furthermore, overexpression of p-AKT using SC79 reversed the effect of sorafenib and MT combination on cell viability and growth of HCC cells. These results suggest that the AKT pathway might be critical for the enhanced anticancer effect observed after co-treatment with MT and sorafenib. Taken together, our findings demonstrated that AKT/p27-mediated cell growth arrest induced by MT increased the sensitivity of HCC cells to the effect of sorafenib.

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p27 Kip1 signaling: Transcriptional and post-translational regulation

Cited by 86 publications

References 41 publications

TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

TRMP, a p53-inducible long noncoding RNA, regulates G1/S cell cycle progression by modulating IRES-dependent p27 translation

ABCE1 is essential for S phase progression in human cells

Melatonin enhances the anti-tumor effect of sorafenib via AKT/p27-mediated cell cycle arrest in hepatocarcinoma cell lines

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