Cytoplasmic sequestration of p53 promotes survival in leukocytes transformed by Theileria

Abstract

The function of the p53 protein as the central effector molecule of the p53 apoptotic pathway was investigated in a reversible model of epigenetic transformation. The infection of bovine leukocytes by the intracellular protozoan parasite Theileria annulata results in parasitedependent transformation and proliferation of the host cells. We found p53 to be largely localized in the host cell cytoplasm and associated with the parasite membrane of isolated schizonts. Curing infected cells of the parasite with the theilericidal drug buparvaquone resulted in a time-dependent translocation of p53 into the host cell nucleus and the upregulation of the proapoptotic Bax and Apaf-1 and the downregulation of the anti-apoptotic Bcl-2 proteins. Although buparvaquone treatment led to apoptosis of the host cell, inhibition of either p53 or Bax significantly reduced buparvaquone-induced apoptosis of the transformed cells. Thus, the p53 apoptotic pathway of host cells is not induced by infection and transformation with Theileria by a mechanism involving cytoplasmic sequestration of p53. The close association of host cell p53 with the parasite membrane implies that the parasite either interacts directly with p53 or mediates cytoplasmic sequestration of p53 by interacting with other host cell proteins regulating p53 localization.

MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes

“…6A). Other workers have reported that p53 in T. parva-infected cells is associated with the schizont membrane (Haller et al, 2010) In T. parva-infected cells, MDM2 was primarily localized to the host nucleoplasm (Fig. 6B).…”

“…However, T. parva-infected cells acquire the ability to proliferate indefinitely, avoiding cell-cycle arrest and apoptosis. Indeed, a recent study by Haller et al (2010) demonstrated that p53-mediated host cell apoptosis is suppressed during Theileria infection, but is rapidly re-activated after elimination of the parasite by the anti-parasitic drug treatment (Haller et al, 2010). Notably, we detected an mRNA in T. parva-infected lymphocytes predicted to encoding a protein homologous to mdm2b, which has been reported to have p53-independent tumorigenicity (Steinman et al, 2004).…”

Theileria-transformed bovine leukocytes have cancer hallmarks

“…T. annulata-transformed leukocytes appear to induce the latter mechanism because TGF-b signaling drives metastasis while altering transcript levels of many TGF-bregulated genes [39], whereas the core signaling components have mostly unaffected expression levels [87]. Theileria parasites are also known to induce the expression of host MYC [34,58], and sequester host p53 in the cytosol [59] to prevent host apoptosis, and these proteins may therefore also play a role in regulating host cell invasiveness.…”

“…Theileria schizonts induce anti-apoptotic proteins such as cellular FLICE-like inhibitory protein (cFLIP) and cellular inhibitor of apoptosis proteins (cIAPs) [25] by activating host IKK complexes [57] and upregulating or maintaining high c-MYC expression [34,58]. Theileria can also inhibit host pro-apoptotic signaling by sequestering host p53 [59] on their cell surface via unknown receptor(s). T. parva infection also confers resistance to Fas/FasLinduced apoptosis [60], which might be crucial for the evasion of cytotoxic T lymphocytes (CTLs) [61] and activation-induced cell death [62].…”

“…Theileria parasites have been shown to sequester p53 on their surface, in the host cytosol, presumably preventing it from executing its role in maintaining genomic stability [59]. The p53 negative regulator Review Trends in Parasitology July 2015, Vol.…”