Molecular Dissection of the 8 Phase Transcriptional Program Controlled by Cyclin E/P220 NPAT Signaling Pathway

2004 ◽  
Author(s):  
Grzegorz Nalepa ◽  
Jeffrey Harper
Keyword(s):  
Signaling Pathway ◽  
Cyclin E ◽  
Molecular Dissection ◽  
Transcriptional Program

scholarly journals RIOK2 Inhibitor NSC139021 Exerts Anti-Tumor Effects on Glioblastoma via Inducing Skp2-Mediated Cell Cycle Arrest and Apoptosis

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1244
Author(s):  
Min Yu ◽  
Xiaoyan Hu ◽  
Jingyu Yan ◽  
Ying Wang ◽  
Fei Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Cyclin E ◽  
Intraperitoneal Administration ◽  
Glioblastoma Cells ◽  
P53 Signaling ◽  
Cycle Arrest ◽  
P53 Signaling Pathway

Up to now, the chemotherapy approaches for glioblastoma were limited. 1-[2-Thiazolylazo]-2-naphthol (named as NSC139021) was shown to significantly inhibit the proliferation of prostate cancer cells by targeting the atypical protein kinase RIOK2. It is documented that RIOK2 overexpressed in glioblastoma. However, whether NSC139021 can inhibit the growth of glioblastoma cells and be a potential drug for glioblastoma treatment need to be clarified. In this study, we investigated the effects of NSC139021 on human U118MG, LN-18, and mouse GL261 glioblastoma cells and the mouse models of glioblastoma. We verified that NSC139021 effectively inhibited glioblastoma cells proliferation, but it is independent of RIOK2. Our data showed that NSC139021 induced cell cycle arrest at G0/G1 phase via the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway in G1/S checkpoint regulation. In addition, NSC139021 also increased the apoptosis of glioblastoma cells by activating the p53 signaling pathway and increasing the levels of Bax and cleaved caspase 3. Furthermore, intraperitoneal administration of 150 mg/kg NSC139021 significantly suppressed the growth of human and mouse glioblastoma in vivo. Our study suggests that NSC139021 may be a potential chemotherapy drug for the treatment of glioblastoma by targeting the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway.

scholarly journals Wnt/β-catenin signaling pathway may regulate cell cycle and expression of cyclin A and cyclin E protein in hepatocellular carcinoma cells

Cell Cycle ◽  
2009 ◽  
Vol 8 (10) ◽  
pp. 1567-1570 ◽  
Author(s):  
Xinhong Wang ◽  
Xiangwei Meng ◽  
Xun Sun ◽  
Mingna Liu ◽  
Shanling Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Signaling Pathway ◽  
Cyclin E ◽  
Cyclin A ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells ◽  
E Protein

Molecular dissection of the RAS/RAF/MAPK pathway in primary and metastatic melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8050-8050
Author(s):  
J. Rother ◽  
J. Bailey ◽  
G. Alvarado ◽  
V. G. Prieto ◽  
A. J. Lazar ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Signaling Pathway ◽  
Braf Mutation ◽  
Mapk Pathway ◽  
Point Mutations ◽  
Initial Diagnosis ◽  
Molecular Dissection ◽  
Braf Mutations ◽  
Mapk Activation ◽  
Metastatic Lesions

8050 Background: Given the reported presence of frequent mutation in NRAS and BRAF in many melanocytic lesions, the association of mutations activating the RAS/RAF/MAPK pathway with tumor progression in melanoma remains unclear. We compared the NRAS and BRAF mutation status with the levels of activated MAPK in paired primary and metastatic melanomas. Methods: 15 patients with material from both primary and metastatic lesions were assessed. Four patients had metastasis at initial diagnosis, the remaining patients developed metastasis from 8.5 to 66 months (mos) following initial diagnosis (median 24.1 mos). Mutations in BRAF (exons 11 and 15) and KRAS and NRAS (exons 1 and 2) were assessed by quantitative pyrosequencing. MAPK levels were assessed by immunohistochemistry on paraffin sections using phosphor-44/42 (Thr202/Tyr204) polyclonal antisera. Results: Activating NRAS point mutations were found in 3 of 15 patients, with 2 detected in the metastatic lesions; both of these had upregulation of activated MAPK compared to the primary lesions. BRAF V599 point mutations were found in 3 of 15 patients and present in both the primary and cognate metastatic lesions. All cases with BRAF or NRAS mutations had moderate to high levels of activated MAPK, as compared to only 2 of 9 patients without such mutations. The correlation of mutational status and clinical course revealed that NRAS/BRAF mutations and/or MAPK activation did not negatively impact overall survival. Conclusions: Molecular alterations in the RAS signaling pathway are associated with activated MAPK in both primary and metastatic melanoma. NRAS mutations and MAPK activation may be preferentially associated with disease progression, as opposed to BRAF mutations. However, neither NRAS/BRAF mutation nor activation of MAPK signaling pathway in primary and/or metastatic melanoma was significantly associated with poor disease outcome. Further molecular dissection using the archived material from two large melanoma neoadjuvant trials conducted in 1988 and 1994 is ongoing to determine the prognostic and predictive power of these biomarkers. No significant financial relationships to disclose.

scholarly journals The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis

2020 ◽  
Vol 117 (52) ◽  
pp. 33486-33495
Author(s):  
Jacob P. Hoj ◽  
Benjamin Mayro ◽  
Ann Marie Pendergast
Keyword(s):  
Heat Shock ◽  
Brain Metastasis ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
Metastatic Tumor ◽  
Brain Parenchyma ◽  
Heat Shock Factor 1 ◽  
Transcriptional Program ◽  
Allosteric Inhibitors ◽  
Pharmacologic Inhibition

Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. Here, we report on the discovery of an actionable signaling pathway utilized by metastatic tumor cells whereby the transcriptional regulator Heat Shock Factor 1 (HSF1) drives a transcriptional program, divergent from its canonical role as the master regulator of the heat shock response, leading to enhanced expression of a subset of E2F transcription factor family gene targets. We find that HSF1 is required for survival and outgrowth by metastatic lung cancer cells in the brain parenchyma. Further, we identify the ABL2 tyrosine kinase as an upstream regulator of HSF1 protein expression and show that the Src-homology 3 (SH3) domain of ABL2 directly interacts with HSF1 protein at a noncanonical, proline-independent SH3 interaction motif. Pharmacologic inhibition of the ABL2 kinase using small molecule allosteric inhibitors, but not ATP-competitive inhibitors, disrupts this interaction. Importantly, knockdown as well as pharmacologic inhibition of ABL2 using allosteric inhibitors impairs expression of HSF1 protein and HSF1-E2F transcriptional gene targets. Collectively, these findings reveal a targetable ABL2-HSF1-E2F signaling pathway required for survival by brain-metastatic tumor cells.

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