Abstract C58: The transglutaminase 2 (TG2) as a new target of p53

Abstract

Abstract The transglutaminase type 2 (TG2) is a multifunctional protein that has been found previously to be upregulated in lung and breast cancer cells in response to DNA damage. Since the tumor suppressor p53 stabilizes and accumulates in the nucleus upon DNA damage, we investigated the relationship of TG2 and p53 in this study. We demonstrated that TG2 is a downstream target of p53. Knockdown of p53 down-regulated the expression of TG2 mRNA and protein. Similarly, over-expression of p53 upregulated the level of TG2 under normal cell culture condition and also with doxorubicin treatment. More importantly, we found that loss of TG2 enables the transformation of primary mammary epithelial cells in a sensitized colony forming assay. In this system, we used primary human mammary epithelial cells (HMECs) that over-express hTERT, SV40 Small T and RasV12; these cells depend only on the loss of p53 activity for full transformation. Interestingly, we observed a synergy in colony formation when both p21 and TG2 were knock-down, and this effect is even more pronounced when there is a deprivation of growth factors. We discovered that insulin and EGF can overcome the effects of p53 in colony formation and the combined loss of TG2 and p21 can replace the absence of insulin in the transformation of HMECs, similar to that of p53 knock-down. This suggests that loss of TG2 potentiates insulin signaling that could be important in cell transformation. Indeed, we showed that loss of TG2 increase the phosphorylation of 4EBP1 at Thr37/46. Our findings indicate that TG2 functions like a tumor suppressor and is an important target of p53. The loss of TG2 results in cell transformation by mimicking insulin signaling. Citation Format: Shi Yun Yeo. The transglutaminase 2 (TG2) as a new target of p53. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C58.