Septin and Ras regulate cytokinetic abscission in detached cells

Area of Science:

• Cell Biology
• Cancer Biology
• Molecular Biology

Background:

• Integrin-mediated adhesion is crucial for cell division (cytokinesis).
• Failure in cytokinesis can lead to tetraploid cells, which are potentially oncogenic.
• This study investigates detachment-induced tetraploid cell formation in human fibroblasts.

Purpose of the Study:

• To analyze the mechanisms preventing and promoting oncogenic tetraploid cell formation upon cell detachment.
• To investigate the role of Ras and SV40LT in anchorage-independent cell division.

Main Methods:

• Analysis of non-transformed human BJ fibroblasts and BJ cells expressing SV40LT (BJ-LT) and/or overactive HRas.
• Observation of cytokinetic abscission, midbody recruitment of ALIX and CHMP4B, and cell division in adherent and detached states.
• Investigation of septin involvement, cytofission, bi-nucleation, senescence, and p53 activation pathways.

Main Results:

• BJ-LT-Ras cells divided when detached, unlike BJ and BJ-LT cells, by recruiting ALIX and CHMP4B to the midbody.
• Septin suppressed furrow regression in detached BJ and BJ-LT cells; re-adhesion led to cytofission, sometimes resulting in bi-nucleated cells.
• Bi-nucleated BJ cells senesced via p53 activation, while BJ-LT cells divided into tetraploids, suggesting PIDDosome pathway involvement in p53 activation.

Conclusions:

• Normal cells possess mechanisms to prevent tetraploidization upon detachment, especially if p53 is functional.
• Viral, mutational, or inflammatory suppression of p53 can lead to oncogenic tetraploid cells.
• Activating Ras mutations enable anchorage-independent cytokinesis in detached transformed cells, promoting tumor growth.