Cables (Cables1), a recently described growth suppressor protein that maps to human chromosome 18q11-12, is lost in many primary colon, lung, and gynecological malignancies. Cultured cell lines that overexpress Cables show a reduction in cell proliferation and Cables(-/-) mice are viable with normal embryonic development. Since Cables expression is lost in primary human tumors and overexpression of Cables suggests a role in growth suppression, we investigated growth properties of primary mouse embryonic fibroblasts (MEFs) from Cables(-/-) and Cables(+/+) mice. Cables(-/-) MEFs exhibited a doubling time of 43-45 hours compared to 73-75 hours for the Cables(+/+)MEFs. Similarly, Cables(-/-) MEFs show a delayed onset of senescence and extension of lifespan, while the Cables(+/+) MEFs ceased proliferating after eight cumulative population doublings. Cables(-/-) MEFs were able to proliferate in low serum concentrations. These data provide convincing evidence that Cables plays a role in the regulation of cell proliferation and survival.