Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis

Abstract

The gene PTTG1 (encoding the pituitary tumor-transforming 1 protein) is overexpressed in several different tumor types, is tumorigenic in vivo and shows transcriptional activity. The PTTG1 protein is cell-cycle regulated and was identified as the human securin (a category of proteins involved in the regulation of sister-chromatid separation) on the basis of biochemical similarities with the Pds1p protein of budding yeast and the Cut2p protein of fission yeast. To unravel the function of human securin in oncogenesis, we carried out a phage-display screening to identify proteins that interact with securin. Notably, we isolated the p53 tumor suppressor. Pull-down and co-immunoprecipitation assays demonstrated that p53 interacts specifically with securin both in vitro and in vivo. This interaction blocks the specific binding of p53 to DNA and inhibits its transcriptional activity. Securin also inhibits the ability of p53 to induce cell death. Moreover, we observed that transfection of H1299 cells with securin induced an accumulation of G2 cells that compensated for the loss of G2 cells caused by transfection with p53. We demonstrated the physiological relevance of this interaction in PTTG1-deficient human tumor cells (PTTG1(-/-)): both apoptotic and transactivating functions of p53 were potentiated in these cells compared to parental cells. We propose that the oncogenic effect of increased expression of securin may result from modulation of p53 functions.

High expression of DNA repair pathways is associated with metastasis in melanoma patients

“…Nuclear accumulation of wild-type p53 has been described in melanoma. Inhibition of p53 transcriptional activity occurs through PTTG1 interaction (Bernal et al, 2002). As shown in Figure 2b, PTTG1 is one of the most overexpressed genes in our melanoma series with bad prognosis.…”

Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2

“…CCNG1 interacts with PPP2CA and dephosphorylates MDM2, resulting in degradation of TRP53, 38 and PPTG1 binds to Trp53 to inhibit Trp53 transcriptional activity 37 and Trp53-mediated cell death. 39 Despite increased expression of these two Trp53 negatively regulating genes, levels of Trp53 remain elevated in the Salmonella-susceptible congenic mice. Additionally, Trp53 can direct E2f2-mediated growth arrest involving the target gene Gadd45.…”

BubR1 is involved in regulation of DNA damage responses

“…Securin is a major molecular target of anaphasepromoting complex/cyclosome (APC/C) (Lew and Burke, 2003;Bharadwaj and Yu, 2004) and it also interacts with p53 (Bernal et al, 2002;Hamid and Kakar, 2003). It has been proposed that the oncogenic effect of increased expression of securin may result from modulation of p53 functions (Bernal et al, 2002).…”

“…It has been proposed that the oncogenic effect of increased expression of securin may result from modulation of p53 functions (Bernal et al, 2002). On the other hand, securin is, in turn, a transcriptional target of p53 (Zhou et al, 2003).…”