Cell proliferation is often regulated by not only external mitogens but also by anti-mitogens, which inhibit cell cycle progression past G1. In normal cells, anti-mitogenic signaling as a result of DNA damage, preventing the cells from replicating and dividing. Tumor cells that are resistant to anti-mitogens allow the cell cycle to move forward when it should be prevented by some anti-mitogenic mechanism. This resistance to anti-mitogens might simply arise from overstimulation by positive mitogens. In other cases, tumor cells possess loss-of-function mutations in some part of the anti-mitogenic pathway. For example, consider the well-known anti-mitogen, transforming growth factor (TGF-𝝱). TGF-𝝱 works by binding to cell-surface receptors and activating the Smad gene regulatory proteins. Smad proteins then trigger an increase in p15, which inhibits cyclin D1 and prevents cell cycle progression. In many cancers, there is a loss-of-function mutation in the Smad proteins, thus negating the entire anti-mitogenic pathway.