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

Hayashida, Kyoko; Kajino, Kiichi; Hattori, Masao; Wallace, Maura; Morrison, Ivan; Greene, Mark I.; Sugimoto, Chihiro

doi:10.1016/j.yexmp.2012.08.008

Cited by 24 publications

(40 citation statements)

References 53 publications

(48 reference statements)

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“…We did not find evidence for changes in the expression of these two miRNAs upon Theileria infection. It is also possible that miRNA targeting of ubiquitination machinery may contribute to other aspects of Theileria -induced host signaling, such as effects on p53 and NFκB pathways [16], [45].…”

Section: Discussionmentioning

confidence: 99%

OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes

et al. 2013

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The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite-induced transformation phenotypes. Tumour progression is a multistep process, yet ‘oncogene addiction’ implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c-Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation.

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Section: Discussionmentioning

confidence: 99%

OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes

et al. 2013

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“…There is evidence that apicomplexan parasites directly target the p53 pathway; for example, Theileria annulata infection was linked to cytoplasmic sequestration of p53 and physical association with parasite membranes (Haller et al, 2010). T. parva -infected lymphocytes have increased levels of MDM2, with alternatively spliced isoforms and impaired DNA damage responses (Hayashida et al, 2013). Parasite-encoded proteins responsible for manipulating host pathways have remained relatively elusive.…”

Section: Pathogen Oncoproteins and Genotoxins And Their Intersection mentioning

confidence: 99%

What’s the Damage? The Impact of Pathogens on Pathways that Maintain Host Genome Integrity

Weitzman

2014

Cell Host & Microbe

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Maintaining genome integrity and transmission of intact genomes is critical for cellular, organismal, and species survival. Cells can detect damaged DNA, activate checkpoints, and either enable DNA repair or trigger apoptosis to eliminate the damaged cell. Aberrations in these mechanisms lead to somatic mutations and genetic instability, which are hallmarks of cancer. Considering the long history of host-microbe coevolution, an impact of microbial infection on host genome integrity is not unexpected, and emerging links between microbial infections and oncogenesis further reinforce this idea. In this review, we compare strategies employed by viruses, bacteria, and parasites to alter, subvert, or otherwise manipulate host DNA damage and repair pathways. We highlight how microbes contribute to tumorigenesis by directly inducing DNA damage, inactivating checkpoint controls, or manipulating repair processes. We also discuss indirect effects resulting from inflammatory responses, changes in cellular metabolism, nuclear architecture, and epigenome integrity, and the associated evolutionary tradeoffs.

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“…NF-kB regulates a multitude of biological processes and is ubiquitously activated in hematological malignancies [14,15]. Pattern-recognition receptors can also activate NF-kB to induce in vivo antimicrobial programs that are crucial for innate and adaptive immunity [16], and many pathogens have the ability to suppress NF-kB signaling [17,18]. The IkB kinase (IKK) complex activates NF-kB, and Theileria schizonts have been shown to constitutively activate the IKK complex on their cell surface, possibly by trans-autophosphorylation [19].…”

Section: Mechanisms Of Theileria-induced Proliferative Signalingmentioning

confidence: 99%

“…Mechanisms of telomerase-dependent immortalization have been the target of intense study in the cancer research community. Telomerase inhibitors effectively restrict T. parva-induced transformation [18]. Recent work has shown that human telomerase, hTERT, can bind to the p65 NF-kB subunit and direct it to a subset of NF-kB The definitive host is a tick (Rhipicephalus for T. parva and Hyalomma for T. annulata), which ingests piroplasms from the blood of an infected bovine host.…”

Section: Reviewmentioning

confidence: 99%

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Theileria-transformed bovine leukocytes have cancer hallmarks

Tretina

Gotia

Mann

et al. 2015

Trends in Parasitology

102

122

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

Cited by 24 publications

References 53 publications

OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes

OncomiR Addiction Is Generated by a miR-155 Feedback Loop in Theileria-Transformed Leukocytes

What’s the Damage? The Impact of Pathogens on Pathways that Maintain Host Genome Integrity

Theileria-transformed bovine leukocytes have cancer hallmarks

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