Mitotic cycle reactivation in terminally differentiated cells by adenovirus infection

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Abstract
Different cell types (e.g., neurons, skeletal and heart myocytes, adipocytes, keratinocytes) undergo terminal differentiation, in which acquisition of specialized functions entails definitive withdrawal from the cell cycle. Such cells are distinct from quiescent (reversibly growth‐arrested) cells, such as contact‐inhibited fibroblasts. Terminally differentiated cells can not be induced to proliferate by means of growth factor stimulation or transduction of cellular oncogenes. An important first step toward defining the molecular basis for such unresponsiveness is to find a practical means to overcome the proliferative block. Furthermore, determining whether terminally differentiated, postmitotic cells still retain a potential competence for proliferation that can be reactivated would have important theoretical and practical implications. To address these questions, we exploited the properties of adenoviruses. These viruses can infect postmitotic cells and express E1A, a powerful activator of proliferation in reversibly growth‐arrested cells. We infected terminally differentiated skeletal muscle cells and adipocytes with human adenovirus type 5 or 12, obtaining full reentry into the cell cycle, including DNA synthesis, mitosis, cytokinesis, and extended proliferation. Similar results were obtained with established cell lines and primary cells belonging to several species, from quail to humans. Genetic analysis indicated that the smaller splice product of E1A, E1A 12S, is sufficient to induce cell cycle reactivation in otherwise permanently nonmitotic cells. These results demonstrate that terminally differentiated cells retain proliferative potential and establish adenovirus as a convenient and powerful means to force such cells to reenter the cell cycle.