Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 21 June 2011
Vol. 4, Issue 178, p. ec169
[DOI: 10.1126/scisignal.4178ec169]


Cell Size Acting with Actin (But Not Akt)

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Cell cycle arrest after DNA damage is typically accompanied by a simultaneous arrest in cell size. Noting that cancer can be associated with not only aberrant cell proliferation but also increased cell size and that the tumor suppressor PTEN has been implicated in regulating cell size—and its arrest following irradiation—Kim et al. explored PTEN’s role in enforcing a cell size checkpoint. Like irradiation, the topoisomerase II inhibitors doxorubicin and etoposide elicited cell cycle arrest in HCT116 human colorectal cancer cells with (HCT116 PTEN+/+) or without (HCT116 PTEN–/–) PTEN. HCT116 PTEN+/+ cells also underwent growth arrest; HCT116 PTEN–/– cells, however, continued to enlarge, arresting at a volume substantially larger than that of their PTEN+/+ counterparts. Cell size arrest after exposure to ionizing radiation was rescued by wild-type PTEN but not by mutants lacking lipid phosphatase ability. PTEN antagonizes phosphatidylinositide 3-kinase (PI3K) signaling, and HCT116 cells harbor an activating mutation in the PI3K catalytic subunit PIK3CA; however, analyses of HCT116 cells with or without wild-type or mutant PI3KCA failed to implicate PI3KCA in the cell size checkpoint. Moreover, mutational analysis revealed that PTEN’s role in the cell size checkpoint was independent of its ability to decrease phosphorylation of Akt (a kinase activated downstream of PI3K), and inhibition of Akt failed to restore size control in PTEN–/– cells. Combining endogenous epitope tagging to create cells that produced FLAG-tagged PTEN with mass spectrometric analysis, the authors identified actin and the actin-binding proteins gelsolin and EPLIN (epithelial protein lost in neoplasm) as interacting with PTEN. Moreover, PTEN coimmunoprecipitated with actin, gelsolin, and EPLIN, and immunofluorescence analysis revealed that GFP-PTEN colocalized with actin at the cell membrane. Pharmacological inhibition of actin remodeling abrogated cell size arrest after exposure of HCT116 PTEN+/+ cells to ionizing radiation, without affecting size arrest of HCT116 PTEN–/– cells. The authors thus conclude that PTEN regulates the DNA damage–induced cell growth arrest checkpoint through a mechanism involving actin remodeling and independent of its regulation of Akt phosphorylation.

J.-S. Kim, X. Xu, H. Li, D. Solomon, W. S. Lane, T. Jin, T. Waldman, Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. Mol. Cell. Biol. 31, 2756–2771 (2011). [PubMed]

Citation: E. M. Adler, Acting with Actin (But Not Akt). Sci. Signal. 4, ec169 (2011).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882