scholarly journals Inhibition of F-Box Protein p45SKP2 Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27KIP1 in Vitamin D Analog-Treated Cancer Cells

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 749-753 ◽  
Author(s):  
Roberto Lin ◽  
Tian Tian Wang ◽  
Wilson H. Miller ◽  
John H. White
Keyword(s):  
Head And Neck ◽  
Cancer Cells ◽  
Gene Transcription ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
P27kip1 Protein ◽  
Protein Levels ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Squamous Carcinoma Cells ◽  
F Box Protein

Treatment of cancer cells with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or its analogs induces growth arrest and expression of the cyclin-dependent kinase inhibitor p27KIP1. Although 1,25(OH)2D3 transiently enhances p27kip1 gene transcription in some cells, its effects on p27KIP1 protein levels are generally more gradual and sustained. This suggests that 1,25(OH)2D3 treatment may be stabilizing p27KIP1 protein, which is sensitive to modification by the SCFSKP2 protein ubiquitin ligase and proteosomal degradation. Here, we show that treatment of AT-84 head and neck squamous carcinoma cells with the 1,25(OH)2D3 analog EB1089 increases p27KIP1 protein levels without significantly affecting expression of its mRNA. EB1089 treatment repressed expression of mRNAs encoding the F-box protein p45SKP2, a marker of poor head and neck cancer prognosis, and the cyclin kinase subunit CKS1, which is essential for targeting p45SKP2 to p27KIP1. This coincided with a reduction of total p45SKP2 protein, and p45SKP2 associated with p27KIP1. Consistent with these findings, turnover of p27KIP1 protein was strongly inhibited in the presence of EB1089. A similar reduction in p45SKP2 expression and stabilization of p27KIP1 protein was observed in 1,25(OH)2D3-sensitive UF-1 promyelocytic leukemia cells, which also respond by transiently increasing p27kip1 gene transcription. Our results reveal that 1,25(OH)2D3 analogs increase levels of p27KIP1 in different cell types by inhibiting expression of SCFSKP2 subunits and reducing turnover of p27KIP1 protein.

scholarly journals Estrogen-mediated epigenetic repression of the imprinted gene cyclin-dependent kinase inhibitor 1C in breast cancer cells

2011 ◽  
Vol 32 (6) ◽  
pp. 812-821 ◽  
Author(s):  
Benjamin A.T. Rodriguez ◽  
Yu-I Weng ◽  
Ta-Ming Liu ◽  
Tao Zuo ◽  
Pei-Yin Hsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Imprinted Gene ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Epigenetic Repression

scholarly journals Ubiquitination of Cyclin-Dependent Kinase Inhibitor, Xic1, is Mediated by the Xenopus F-box Protein xSkp2

Cell Cycle ◽  
2006 ◽  
Vol 5 (3) ◽  
pp. 304-314 ◽  
Author(s):  
Horng-Ru Lin ◽  
Li-Chiou Chuang ◽  
Hector Boix-Perales ◽  
Anna Philpott ◽  
P. Renee Yew
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
F Box Protein

scholarly journals Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3110 ◽  
Author(s):  
Sakiko Nishikawa ◽  
Yuka Itoh ◽  
Muneshige Tokugawa ◽  
Yasumichi Inoue ◽  
Ken-ichi Nakashima ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Fate ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Sophora Flavescens ◽  
Promoter Activation ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Stress Relieving ◽  
A Cell ◽  
Cellular Stresses

In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.

scholarly journals Increased Expression of NPM1 Suppresses p27Kip1 Function in Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2886
Author(s):  
Tatsuya Kometani ◽  
Takuya Arai ◽  
Taku Chibazakura
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Significant Suppression ◽  
Mouse Xenograft ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Xenograft Models ◽  
Low Levels ◽  
Proteomic Screening

p27Kip1, a major cyclin-dependent kinase inhibitor, is frequently expressed at low levels in cancers, which correlates with their malignancy. However, in this study, we found a qualitative suppression of p27 overexpressed in some cancer cells. By proteomic screening for factors interacting with p27, we identified nucleophosmin isoform 1 (NPM1) as a novel p27-interacting factor and observed that NPM1 protein was expressed at high levels in some cancer cells. NPM1 overexpression in normal cells suppressed p27 function, and conversely, NPM1 knockdown in cancer cells restored the function in vitro. Furthermore, the tumors derived from cancer cells carrying the combination of p27 overexpression and NPM1 knockdown constructs showed significant suppression of growth as compared with those carrying other combinations in mouse xenograft models. These results strongly suggest that increased expression of NPM1 qualitatively suppresses p27 function in cancer cells.

Sign in / Sign up

Export Citation Format

Share Document