The Mechanism of Full Activation of Tumor Suppressor PTEN at the Phosphatidylinositol-Enriched Membrane

2021 ◽  
Author(s):  
Hyunbum Jang ◽  
Iris Nira Smith ◽  
Charis Eng ◽  
Ruth Nussinov
Keyword(s):  
Tumor Suppressor ◽  
Full Activation

scholarly journals The mechanism of full activation of tumor suppressor PTEN at the phosphatidylinositol-enriched membrane

2021 ◽  
Author(s):  
Hyunbum Jang ◽  
Iris Nira Smith ◽  
Charis Eng ◽  
Ruth Nussinov
Keyword(s):  
Drug Discovery ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Full Length ◽  
Detailed Mechanism ◽  
Explicit Solvent ◽  
Signaling Lipids ◽  
Cell Growth And Proliferation ◽  
First Time ◽  
Full Activation

AbstractTumor suppressor PTEN dephosphorylates signaling lipid PIP3 produced by PI3Ks. Abundant PIP3 promotes cell growth and proliferation. PTEN is the second most highly mutated protein in cancer and is drugless. The detailed mechanism at the membrane of this pivotal phosphatase is unknown hindering understanding and drug discovery. Here for the first time, exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane, its interaction with membranes composed of zwitterionic phosphatidylcholine and anionic phosphatidylserine and phosphatidylinositol, including signaling lipids PIP2 and PIP3, and moving away from the zwitterionic and getting absorbed onto the anionic membrane that harbors the PIP3. PIP3 then allosterically unfolds the N-terminal PIP2 binding domain, translocating it to the membrane where its polybasic motif interacts with PIP2, localizing on microdomains enriched in signaling lipids, as PI3K does. Finally, we determined PTEN catalytic action at the membrane, all in line with available experimental observations.

scholarly journals Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL

2016 ◽  
Vol 7 (2) ◽  
pp. e2083-e2083 ◽  
Author(s):  
J Le Pen ◽  
M Laurent ◽  
K Sarosiek ◽  
C Vuillier ◽  
F Gautier ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Cellular Stress ◽  
Clinical Use ◽  
Tumor Suppressor P53 ◽  
Family Network ◽  
Bh3 Mimetics ◽  
Stress Signals ◽  
Full Activation ◽  
Bh3 Mimetic

Abstract Proapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.

scholarly journals The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

iScience ◽  
2021 ◽  
pp. 102438
Author(s):  
Hyunbum Jang ◽  
Iris Nira Smith ◽  
Charis Eng ◽  
Ruth Nussinov
Keyword(s):  
Tumor Suppressor ◽  
Full Activation

CENP-C: An oncogene or tumor suppressor gene? A possible new tumor marker

2001 ◽  
Vol 120 (5) ◽  
pp. A299-A299
Author(s):  
D KAZANOV ◽  
B STERN ◽  
W PYERIN ◽  
O BOECHER ◽  
H STRUL ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Marker ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene

625: Bert-Hogg-Dubé (BHD) Tumor Suppressor Expression in Sporadic Renal Cell Carcinomas

2005 ◽  
Vol 173 (4S) ◽  
pp. 170-171 ◽  
Author(s):  
Dakun Wang ◽  
Jorge L. Yao ◽  
Edward M. Messing ◽  
Susan R. Schoen ◽  
Xiangrong He ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Renal Cell ◽  
Renal Cell Carcinomas
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