Temporary disruption of the plasma membrane is required for c-fos expression in response to mechanical stress

Mechanically stressed cells display increased levels of fos message and pro tein. Although the intracellular signaling pathways responsible for FOS ind uction have been extensively characterized, we still do not understand the nature of the primary cell mechanotransduction event responsible for conver ting an externally acting mechanical stressor into an intracellular signal cascade. We now report that plasma membrane disruption (PMD) is quantitativ ely correlated on a cell-by-cell basis with fos protein levels expressed in mechanically injured monolayers. When the population of PMD-affected cells in injured monolayers was selectively prevented from responding to the inj ury, the fos response was completely ablated, demonstrating that PMD is a r equisite event. This PMD-dependent expression of fos protein did not requir e cell exposure to cues inherent in release from cell-cell contact inhibiti on or presented by denuded substratum, because it also occurred in subconfl uent monolayers. Fos expression also could not be explained by factors rele ased through PMD, because cell injury conditioned medium failed to elicit f os expression. Translocation of the transcription factor NF-kappa B into th e nucleus may also be regulated by PMD, based on a quantitative correlation similar to that found with fos. We propose that PMD by allowing a flux of normally impermeant molecules across the plasma membrane, mediates a previo usly unrecognized form of cell mechanotransduction. PMD may thereby lead to cell growth or hypertrophy responses such as those that are present normal ly in mechanically stressed skeletal muscle and pathologically in the cardi ovascular system.