P53Deficiency-induced Smad1over Expression Plays Important Roles In Tumorigenesis And Chemosensitivity

The DNA damage response helps to maintain genome integrity, suppresstumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previousstudies have shown that Smad1is activated by Atm in DNA damage response, whichbinds to p53and promotes its stabilization. Here we report another aspect of theinterplay between p53and Smad1. p53deficiency results in an increase in Smad1expression in human rectal cancer samples and mouse embryonic fibroblast. UsingMEFs as a model, we found that knockdown of Smad1, but not Smad5, in p53-/-MEFsfurther promotes cell proliferation, E1A/Ras-induced cell transformation, andtumorigenesis in nude mouse, indicating that elevated Smad1helps to inhibitproliferation and tumorigenesis in the absence of p53, and suggesting that up-regulationof Smad1may act as a feedback compensation for the loss of p53. In addition, elevatedSmad1appears to have a negative effect on chemotherapy, as tumors developed fromSmad1but not Smad5knockdown cells and primary rectal cells with Smad1knockeddown showed increased sensitivity to Dox treatment, which is correlated withdecreased cell proliferation and/or survival of tumor cells. These findings underscorethe significance of Smad1-p53interaction in tumor suppression and also reveal anunexpected role for Smad1in chemoresistance of rectal cancer.