scholarly journals Lyn Tyrosine Kinase Inhibits Nuclear Export of the p53 Tumor Suppressor

2002 ◽  
Vol 1 (6) ◽  
pp. 703-708 ◽  
Author(s):  
Xinping Ren ◽  
Cheng Cao ◽  
Liben Zhu ◽  
Kiyotsugu Yoshida ◽  
Surender Kharbanda ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tyrosine Kinase ◽  
Nuclear Export ◽  
P53 Tumor Suppressor ◽  
Lyn Tyrosine Kinase

scholarly journals CSIG-07. c-Src PHOSPHORYLATES AND INACTIVATES THE CIC TUMOR SUPPRESSOR PROTEIN IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii29-ii29
Author(s):  
Severa Bunda ◽  
Pardeep Heir ◽  
Annie Li ◽  
Mamatjan Yasin ◽  
Gelareh Zadeh ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Receptor Tyrosine Kinase ◽  
Nuclear Export ◽  
Kinase Inhibitor ◽  
Erk Pathway ◽  
Tumor Suppressor Function ◽  
Downstream Effector ◽  
Kinase C

Abstract Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/MEK/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degradation of CIC in glioblastoma (GBM). In this study, we examined whether another important downstream effector of RTK/EGFR, the non-receptor tyrosine kinase c-Src, affects CIC repressor function in GBM. We found that c-Src binds and tyrosine phosphorylates CIC on residue 1455 to promote nuclear export of CIC. On the other hand, CIC mutant allele (CIC-Y1455F), that escapes c-Src-mediated tyrosine phosphorylation, remains localized to the nucleus and retains strong repressor function against CIC targets, the oncogenic ETV transcription factors. Furthermore, we show that the orally available Src family kinase inhibitor, dasatinib, which prevents EGF-mediated tyrosine phosphorylation of CIC and attenuates elevated ETV levels, reduces viability of GBM cells and glioma stem cells (GSC), but not of their control cells with undetectable c-Src activity. In fact, GBM cells and GSC expressing the tyrosine-defective CIC mutant (Y1455F) lose sensitivity to dasatinib, further endorsing the effect of dasatinib on Src-mediated tyrosine phosphorylation of CIC. Importantly we show that combined inhibition of Src and MEK/ERK results in greatest stabilization of CIC and attenuation of proliferation compared to either inhibitor alone. These findings elucidate important mechanisms of CIC regulation and provide the rationale to target c-Src alongside ERK pathway inhibitors as a way to fully restore CIC tumor suppressor function in neoplasms such as GBM.

Targeting the p53 tumor suppressor activity in glioblastomas using small molecule MDM2-inhibitor

2011 ◽  
Vol 42 (01) ◽  
Author(s):  
P. Monfared ◽  
T. Viel ◽  
G. Schneider ◽  
Y. Waerzeggers ◽  
S. Rapic ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Small Molecule ◽  
Suppressor Activity ◽  
P53 Tumor Suppressor ◽  
Tumor Suppressor Activity ◽  
Mdm2 Inhibitor

scholarly journals BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer’s Disease

2015 ◽  
Vol 16 (2) ◽  
pp. 2879-2892 ◽  
Author(s):  
Atsuko Nakanishi ◽  
Akari Minami ◽  
Yasuko Kitagishi ◽  
Yasunori Ogura ◽  
Satoru Matsuda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tumor Suppressor ◽  
P53 Tumor Suppressor
Sign in / Sign up

Export Citation Format

Share Document