scholarly journals Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

2014 ◽  
Vol 111 (24) ◽  
pp. 8832-8837 ◽  
Author(s):  
O. V. Leontieva ◽  
Z. N. Demidenko ◽  
M. V. Blagosklonny
Keyword(s):  
Cell Density ◽  
High Cell Density ◽  
Mammalian Target Of Rapamycin ◽  
Contact Inhibition ◽  
Target Of Rapamycin ◽  
High Cell ◽  
Senescence Program

scholarly journals Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

Oncogene ◽  
2001 ◽  
Vol 20 (22) ◽  
pp. 2727-2736 ◽  
Author(s):  
Masaya Baba ◽  
Syu-ichi Hirai ◽  
Satoshi Kawakami ◽  
Takeshi Kishida ◽  
Naoki Sakai ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Cell Density ◽  
High Cell Density ◽  
Contact Inhibition ◽  
Tumor Suppressor Protein ◽  
High Cell

scholarly journals Cyclin E restores p53 activity in contact-inhibited cells.

1995 ◽  
Vol 15 (7) ◽  
pp. 3926-3933 ◽  
Author(s):  
A Deffie ◽  
M Hao ◽  
R Montes de Oca Luna ◽  
D L Hulboy ◽  
G Lozano
Keyword(s):  
Cell Cycle ◽  
Cell Density ◽  
Transcriptional Activity ◽  
High Cell Density ◽  
P53 Protein ◽  
Cyclin E ◽  
Ectopic Expression ◽  
Contact Inhibition ◽  
High Cell ◽  
Inhibition Of Growth

The wild-type p53 protein is a potent growth suppressor when overexpressed in vitro. It functions as a transcriptional activator and causes growth arrest at the G1/S stage of the cell cycle. We monitored p53 transactivation as an indicator of p53 function throughout the cell cycle. We first demonstrate that cells which exhibited contact inhibition of growth lacked p53 transactivation function at high cell density. Since these cells were noncycling, we examined whether the ectopic expression of any cyclin could override contact inhibition of growth and restore p53 transactivation function. The transfection of cyclin E at high cell density stimulated the progression of cells through the cell cycle and restored p53 transactivation function. The transcriptional activity of p53 induced by cyclin E was regulated at the level of DNA binding. Cells that did not show contact inhibition of growth had a functional p53 regardless of cell density. Thus, contact inhibition of cell growth corresponded to a lack of p53 transactivation function and the overexpression of cyclin E in these contact-inhibited cells stimulated cell cycle progression and resulted in p53 transcriptional activity.

scholarly journals AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation

2021 ◽  
Vol 4 (10) ◽  
pp. e202000953
Author(s):  
Daehee Hwang ◽  
Miju Kim ◽  
Soyeon Kim ◽  
Mi Ra Kwon ◽  
Ye-Seul Kang ◽  
...  
Keyword(s):  
Cell Density ◽  
High Cell Density ◽  
Hippo Pathway ◽  
Contact Inhibition ◽  
Cell Junctions ◽  
Hippo Signaling ◽  
High Cell ◽  
Downstream Effector ◽  
Tightly Coupled ◽  
Cell Growth And Differentiation

Contact inhibition is a key cellular phenomenon that prevents cells from hyper-proliferating upon reaching confluence. Although not fully characterized, a critical driver of this process is the Hippo signaling pathway, whose downstream effector yes-associated protein plays pivotal roles in cell growth and differentiation. Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. Mono-ubiquitinated AMOTL2, in turn, interacts with the kinase LATS2, which facilitates recruitment of the upstream Hippo pathway component SAV1 and ultimately promotes yes-associated protein phosphorylation and subsequent cytoplasmic sequestration and/or degradation. Furthermore, contact inhibition induced by high cell density promoted the localization and stabilization of WWP1 at cell junctions, where it interacted with Crumbs polarity proteins. Notably, the Crumbs complex was functionally important for AMOTL2 mono-ubiquitination and LATS activation under high cell density conditions. These findings delineate a functionally important molecular mechanism in which AMOTL2 mono-ubiquitination by WWP1 at cell junctions and LATS activation are tightly coupled to upstream cell density cues.

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