Targeted repression of bone morphogenetic protein 7, a novel target of the p53 family, triggers proliferative defect in p53-deficient breast cancer cells.
p53 tumor suppressor and its family members, p63 and p73, are known to play a role in the survival of cells exposed to stress signals. As a transcription factor, the p53 family proteins induce a plethora of target genes that mediate their functions in the cell cycle, apoptosis, and other biological activities. However, the mechanism by which the p53 family proteins regulate their cell survival functions is still not clear. Here, we showed that bone morphogenetic protein 7 (BMP7) is a novel target gene regulated by the p53 family and mediates the cell survival function of the basal physiologically relevant level of p53. Specifically, we found that knockdown of BMP7 markedly inhibits the proliferation of p53-deficient, but not p21-knockdown, breast cancer cells compared with the ones with wild-type p53. In addition, we found that inhibitor of differentiation or DNA binding 2 (Id2), a transcription factor implicated for cell survival, is regulated by the BMP7 and p53 pathways. Interestingly, whereas a functional BMP7 or p53 pathway is sufficient to maintain the basal level of Id2 expression, loss of both pathways abrogates Id2 expression. Furthermore, we showed that overexpression of Id2 can restore p53-deficient cells to survive in the absence of BMP7. As a result, we identified a previously unrecognized role for BMP7 in the maintenance of cell survival for p53-deficient cells, at least in part, through Id2. Together, we hypothesize that breast cancer patients with mutant p53 might benefit from targeted repression of BMP7 expression and/or targeted inhibition of the BMP7 pathway.
Yan
Wensheng
W
Center for Comparative Oncology, University of California at Davis, Davis, California 95616, USA.
Chen
Xinbin
X
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53