scholarly journals RAS-mediated suppression of PAR3 and its effects on SCC initiation and tissue architecture occur independently of hyperplasia

2020 ◽  
Vol 133 (23) ◽  
pp. jcs249102
Author(s):  
Ji Ling ◽  
Maria Sckaff ◽  
Manisha Tiwari ◽  
Yifang Chen ◽  
Jingting Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Division ◽  
Mapk Pathway ◽  
Temporal Analysis ◽  
Current Evidence ◽  
Spindle Orientation ◽  
Tissue Architecture ◽  
Spatial Cues ◽  
Human Squamous Cell Carcinoma ◽  
E Cadherin

ABSTRACTProper epithelial development and homeostasis depends on strict control of oriented cell division. Current evidence shows that this process is regulated by intrinsic polarity factors and external spatial cues. Owing to the lack of an appropriate model system that can recapitulate the architecture of the skin, deregulation of spindle orientation in human epithelial carcinoma has never been investigated. Here, using an inducible model of human squamous cell carcinoma (SCC), we demonstrate that RAS-dependent suppression of PAR3 (encoded by PARD3) accelerates epithelial disorganization during early tumorigenesis. Diminished PAR3 led to loss of E-cadherin-mediated cell adhesion, which in turn contributed to misoriented cell division. Pharmacological inhibition of the MAPK pathway downstream of RAS activation reversed the defects in PAR3 expression, E-cadherin-mediated cell adhesion and mitotic spindle orientation. Thus, temporal analysis of human neoplasia provides a powerful approach to study cellular and molecular transformations during early oncogenesis, which allowed identification of PAR3 as a critical regulator of tissue architecture during initial human SCC development.

scholarly journals E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

2017 ◽  
Vol 114 (29) ◽  
pp. E5845-E5853 ◽  
Author(s):  
Kevin C. Hart ◽  
Jiongyi Tan ◽  
Kathleen A. Siemers ◽  
Joo Yong Sim ◽  
Beth L. Pruitt ◽  
...  
Keyword(s):  
Cell Division ◽  
Cell Monolayer ◽  
Spindle Orientation ◽  
Tissue Cell ◽  
Cellular Behavior ◽  
Cell Monolayers ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Tensile Forces ◽  
E Cadherin

Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin–Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell–cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of E-cadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.

scholarly journals Cell division orientation is coupled to cell–cell adhesion by the E-cadherin/LGN complex

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Martijn Gloerich ◽  
Julie M. Bianchini ◽  
Kathleen A. Siemers ◽  
Daniel J. Cohen ◽  
W. James Nelson
Keyword(s):  
Cell Adhesion ◽  
Cell Division ◽  
E Cadherin ◽  
Cell Cell

scholarly journals Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia

2009 ◽  
Vol 20 (16) ◽  
pp. 3740-3750 ◽  
Author(s):  
Nicole den Elzen ◽  
Carmen V. Buttery ◽  
Madhavi P. Maddugoda ◽  
Gang Ren ◽  
Alpha S. Yap
Keyword(s):  
Cell Division ◽  
Asymmetric Cell Division ◽  
Spindle Orientation ◽  
Mitotic Spindles ◽  
Spatial Cues ◽  
Adhesion Receptors ◽  
Interacting Protein ◽  
Division Plane ◽  
Oriented Cell Division ◽  
Tissue Organization

Oriented cell division is a fundamental determinant of tissue organization. Simple epithelia divide symmetrically in the plane of the monolayer to preserve organ structure during epithelial morphogenesis and tissue turnover. For this to occur, mitotic spindles must be stringently oriented in the Z-axis, thereby establishing the perpendicular division plane between daughter cells. Spatial cues are thought to play important roles in spindle orientation, notably during asymmetric cell division. The molecular nature of the cortical cues that guide the spindle during symmetric cell division, however, is poorly understood. Here we show directly for the first time that cadherin adhesion receptors are required for planar spindle orientation in mammalian epithelia. Importantly, spindle orientation was disrupted without affecting tissue cohesion or epithelial polarity. This suggests that cadherin receptors can serve as cues for spindle orientation during symmetric cell division. We further show that disrupting cadherin function perturbed the cortical localization of APC, a microtubule-interacting protein that was required for planar spindle orientation. Together, these findings establish a novel morphogenetic function for cadherin adhesion receptors to guide spindle orientation during symmetric cell division.

622: Von Hippel-Lindau Inactivation Downregulates the Cell-Cell Adhesion Molecule E Cadherin in Renal Cancer Cells

2005 ◽  
Vol 173 (4S) ◽  
pp. 170-170
Author(s):  
Maxine G. Tran ◽  
Miguel A. Esteban ◽  
Peter D. Hill ◽  
Ashish Chandra ◽  
Tim S. O'Brien ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Von Hippel Lindau ◽  
E Cadherin ◽  
Cell Cell
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