scholarly journals Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors

2020 ◽  
Vol 11 (5) ◽  
pp. 583-590
Author(s):  
Yan Yin ◽  
Yuxing Sun ◽  
Lianhua Zhao ◽  
Jinpeng Pan ◽  
Yangbo Feng
Keyword(s):  
Ribosomal Protein ◽  
Therapeutic Target ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Computer Aided ◽  
Attractive Therapeutic Target ◽  
Ribosomal Protein S6 Kinase

Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target.

The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-α in 3T3-L1 adipocytes and is a target for transactivation by PPARγ

2006 ◽  
Vol 291 (1) ◽  
pp. E115-E127 ◽  
Author(s):  
Ji Young Kim ◽  
Kristin Tillison ◽  
Jun-Ho Lee ◽  
David A. Rearick ◽  
Cynthia M. Smas
Keyword(s):  
Adipose Tissue ◽  
Ribosomal Protein ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
S6 Kinase ◽  
Triglyceride Lipase ◽  
Ribosomal Protein S6 ◽  
Tnf Α ◽  
Adipose Tissue Triglyceride ◽  
Ribosomal Protein S6 Kinase

The minimal adipose phenotype of hormone-sensitive lipase (HSL)-null mice suggested that other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose tissue triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2ζ/TTS2.2 (ATGL). We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF-α and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPARγ. Insulin at 100 nM resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI 3-kinase and p70 ribosomal protein S6 kinase. TNF-α treatment decreased ATGL transcript in a time-dependent manner that paralleled TNF-α downregulation of PPARγ with a maximal decrease noted by 6 h. TNF-α effects on ATGL were attenuated by pretreatment with PD-98059, LY-294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI 3-kinase, and p70 ribosomal protein S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2,979 bp of the murine ATGL 5′-flanking region. Compared with promoterless pGL2-Basic, the −2979/+21 ATGL luciferase construct demonstrated 120- and 40-fold increases in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of eight ATGL promoter deletions revealed that the −928/+21, −1738/+21, −1979/+21, and −2979/+21 constructs were transactivated by PPARγ. Our findings identify the novel lipase ATGL to be a target gene for TNF-α and insulin action in adipocytes and reveal that it is subject to transcriptional control by PPARγ-mediated signals.

scholarly journals pS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer

2019 ◽  
Vol 8 (7) ◽  
pp. 863-869
Author(s):  
Chan Sub Park ◽  
Jihye Choi ◽  
Min-Ki Seong ◽  
Sung-Eun Hong ◽  
Jae-Sung Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ribosomal Protein ◽  
Growth Factor Receptor ◽  
Gonadotropin Releasing Hormone ◽  
S6 Kinase ◽  
Releasing Hormone ◽  
Gonadotropin Releasing Hormone Agonist ◽  
Ribosomal Protein S6 ◽  
Epidermal Growth ◽  
Ribosomal Protein S6 Kinase

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Regulation and localization of ribosomal protein S6 kinase 1 isoforms

2009 ◽  
Vol 27 (1) ◽  
pp. 12-21 ◽  
Author(s):  
Doyil Kim ◽  
Argun Akcakanat ◽  
Gopal Singh ◽  
Chandeshwar Sharma ◽  
Funda Meric-Bernstam
Keyword(s):  
Ribosomal Protein ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

High mobility group box 2 regulates skeletal muscle development through ribosomal protein S6 kinase 1

2020 ◽  
Vol 34 (9) ◽  
pp. 12367-12378 ◽  
Author(s):  
Ying Fang ◽  
Feng Liang ◽  
Renqiang Yuan ◽  
Qi Zhu ◽  
Shufang Cai ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ribosomal Protein ◽  
Muscle Development ◽  
High Mobility ◽  
High Mobility Group ◽  
Skeletal Muscle Development ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase
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