Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook, Betheney R.; Barr, Alexis R.

doi:10.1101/2021.05.06.442976

Cited by 2 publications

(2 citation statements)

References 64 publications

(107 reference statements)

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“…Mechanistically, COPS5 mediated the degradation of P27 in a proteasome-dependent manner, thereby controlling its stability. P27 is a universal cyclin-dependent kinase (CDK) inhibitor that directly inhibits the enzymatic activity of the cyclin-CDK complex, resulting in cell cycle arrest in the G1 phase [20][21][22] . In our study, we also found that knocking down EEF1D can lead to cell G1/S phase arrest, and a decrease in CDK4, CDK6 and CyclinD1 proteins, which is closely related to EEF1D activation of the COPS5/P27 pathway, resulting in an increase in P27 proteins.…”

Section: Discussionmentioning

confidence: 99%

LncRNA SNHG6 binds to EEF1D through COPS5/P27 pathway to affect the cycle and proliferation of hepatocellular carcinoma

Ma,

Liu,

et al. 2023

Preprint

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Our previous work had suggested that LncRNA SNHG6 interacted with COPS5 and their expression was positively correlated in hepatocellular carcinoma(HCC). In this study we found that SNHG6 and COPS5 was upregulated in HCC patients, and patients with high expression of SNHG6 and COPS5 had worse overall survival(OS). After RNA pulldown experiments and mass spectrometry analysis of SNHG6, and CO-IP experiments and mass spectrometry analysis of COPS5, we finally determined that EEF1D interacted both SNHG6 and COPS5. EEF1D, which had high expression in HCC tissues and cell lines, was related to poor prognosis. Meanwhile, SNHG6, EEF1D and COPS5 could affect the cell cycle and promote proliferation of HCC. Subcutaneous tumors grown from SNHG6-knockdown cells were inhibited compared to control cells. Knocking down SNHG6 or EEF1D leads to faster degradation of COPS5 protein, and activate COPS5/P27 pathway. The first domain leucine zipper of EEF1D was the binding site to COPS5. Eventually, SNHG6 binds to EEF1D and stabilize COPS5 and activate the P27 pathway, affecting the cell cycle to accelerate cell proliferation. SNHG6 may serve as a new target for the diagnosis and treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

LncRNA SNHG6 binds to EEF1D through COPS5/P27 pathway to affect the cycle and proliferation of hepatocellular carcinoma

Ma,

Liu,

et al. 2023

Preprint

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“…This article has no additional data. The data are provided in the electronic supplementary material [70].…”

Section: Data Accessibilitymentioning

confidence: 99%

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Pennycook

Barr

2021

Open Biol.

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The use of CDK4/6 inhibitors in the treatment of a wide range of cancers is an area of ongoing investigation. Despite their increasing clinical use, there is limited understanding of the determinants of sensitivity and resistance to these drugs. Recent data have cast doubt on how CDK4/6 inhibitors arrest proliferation, provoking renewed interest in the role(s) of CDK4/6 in driving cell proliferation. As the use of CDK4/6 inhibitors in cancer therapies becomes more prominent, an understanding of their effect on the cell cycle becomes more urgent. Here, we investigate the mechanism of action of CDK4/6 inhibitors in promoting cell cycle arrest. Two main models explain how CDK4/6 inhibitors cause G1 cell cycle arrest, which differ in their dependence on the CDK inhibitor proteins p21 and p27. We have used live and fixed single-cell quantitative imaging, with inducible degradation systems, to address the roles of p21 and p27 in the mechanism of action of CDK4/6 inhibitors. We find that CDK4/6 inhibitors can initiate and maintain a cell cycle arrest without p21 or p27. This work clarifies our current understanding of the mechanism of action of CDK4/6 inhibitors and has implications for cancer treatment and patient stratification.

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Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

Cited by 2 publications

References 64 publications

LncRNA SNHG6 binds to EEF1D through COPS5/P27 pathway to affect the cycle and proliferation of hepatocellular carcinoma

LncRNA SNHG6 binds to EEF1D through COPS5/P27 pathway to affect the cycle and proliferation of hepatocellular carcinoma

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

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