p53 promotes apoptosis in response to death stimuli by transactivation of target genes and transcription-independent mechanisms. We recently showed that wild-type rapidly translocates mitochondria multiple cultured cells. Mitochondrial physically interacts with antiapoptotic Bcl proteins, induces Bak oligomerization, permeabilizes mitochondrial membranes, cytochrome c release. Here we characterize the vivo. Mice were subjected γ irradiation or intravenous etoposide administration, followed...

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use mouse model pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on for growth reduced and manifested in suppression antitumor immunity. KRAS-deficient cells retain ability form tumors immunodeficient mice. However, they fail evade host immune system syngeneic wild-type mice, triggering...

Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as high, upstream activator cells within the innate adaptive immunological systems. Recent studies have suggested potentially broader role for MIF in growth regulation because its ability to antagonize p53-mediated gene activation apoptosis. To better understand MIF's activity control, we generated characterized strain MIF-knockout (MIF-KO) mice inbred, C57BL/6 background. Embryonic fibroblasts from...

A cDNA library enriched with Myc-responsive cDNAs but depleted of myc was used in a functional screen for growth enhancement c-myc-null cells. clone mitochondrial serine hydroxymethyltransferase (mSHMT) that capable partial complementation the defects cells identified. Expression analysis and chromatin immunoprecipitation demonstrated mSHMT is direct Myc target gene. Furthermore, separate gene encoding cytoplasmic isoform same enzyme also regulation. SHMT enzymes are major source one-carbon...

Genetically or epigenetically defined reprogramming is a hallmark of cancer cells. However, causal association between genome and has not yet been conclusively established. In particular, little known about the mechanisms that underlie metastasis cancer, even less identity metastasizing this study, we used model conditional expression oncogenic KrasG12D allele in primary mouse cells to show dedifferentiation fundamental early step malignant transformation initiation. Our data indicate stable...

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing in KrasG12D/Trp53R172H-driven tumors resulted infiltration cells, complete regression, 100% survival immunocompetent host mice. By contrast, Pik3ca-null implanted...

A dichotomy exists regarding the role of signal transducer and activator transcription 3 (STAT3) in cancer. Functional genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types These contrasting actions imply context dependency. To examine mechanisms that underlie function cancer, we evaluated impact activity KRAS-driven lung pancreatic Our study defines fundamental previously unrecognized maintenance epithelial cell identity...

TP73, despite significant homology to TP53, is not a classic tumor suppressor gene, since it exhibits upregulation of nonmutated products in human tumors and lacks phenotype p73-deficient mice. We recently reported that an N-terminally truncated isoform, DeltaNp73, upregulated breast gynecological cancers. further showed DeltaNp73 potent transdominant inhibitor wild-type p53 TAp73 cultured cells by efficiently counteracting their target gene transactivations, apoptosis, growth suppression...

Significance Pancreatic cancer is characterized by aggressive growth and a high propensity for metastatic spread. Despite growing understanding of the genetic causes pancreatic cancer, mechanism timing metastasis, main cause deaths in patients, remain relatively unexplored. In this study, we used experimental mouse models carcinogenesis to show that hyperactivation Ras/MAPK/ERK pathway stabilization MYC protein are two driving forces behind development cells with potential. Our results...

Abstract Complex proapoptotic functions are essential for the tumor suppressor activity of p53. We recently described a novel transcription-independent mechanism that involves rapid action p53 at mitochondria and executes shortest known circuitry death signaling. Here, we examine if this p53-dependent mitochondrial program could be exploited suppression in vivo. To test this, engage Eμ-Myc transgenic mice, well-established model lymphomagenesis. show exclusive delivery to outer membrane...

Macrophage migration inhibitory factor (MIF) has been shown to functionally inactivate the p53 tumor suppressor and inhibit p53-responsive gene expression apoptosis. To better understand role of MIF in cell growth biology, we evaluated MIF-null embryonic fibroblasts with respect their immortalization transformation properties. Although minor deviations characteristics MIF−/−fibroblasts were observed under normal culture conditions, MIF-deficient cells growth-impaired following introduction...

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, metastatic disease with limited treatment options. Factors contributing to the predisposition and therapy resistance in pancreatic cancer are not well understood. Here, we used mouse model of KRAS-driven carcinogenesis define distinct subtypes PDAC metastasis: epithelial, mesenchymal quasi-mesenchymal. We examined pro-survival signals these cells therapeutic response differences between them. Our data indicate that initiation...

Mice engineered to express c-Myc in B cells (Emu-myc mice) develop lethal lymphomas which the gene encoding p53 tumor suppressor is frequently mutated. Whether homolog p73 also functions as a vivo remains controversial. Here we have shown that loss does not substantially affect disease onset and mortality Emu-myc mice. However, it alter phenotype of disease. Specifically, decreased nodal increased widespread extranodal dissemination. We further found acted dominant during Emu-myc-driven cell...

Oncogenic mutations in KRAS are among the most common cancer. Classical models suggest that loss of epithelial characteristics and acquisition mesenchymal traits associated with cancer aggressiveness therapy resistance. However, mechanistic link between these phenotypes mutant biology remains to be established. Here, we identify STAT3 as a genetic modifier TGF-beta-induced transition. Gene expression profiling pancreatic cells identifies more than 200 genes commonly regulated by oncogenic...

Oncogenic mutations in KRAS are among the most common cancer. Classical models suggest that loss of epithelial characteristics and acquisition mesenchymal traits associated with cancer aggressiveness therapy resistance. However, mechanistic link between these phenotypes mutant biology remains to be established. Here, we identify STAT3 as a genetic modifier TGF-beta-induced transition. Gene expression profiling pancreatic cells identifies more than 200 genes commonly regulated by oncogenic...

Macrophage migration inhibitory factor (MIF) is a ubiquitously expressed pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. We used genetic approach to show deletion MIF gene mice several major consequences for proliferative transforming properties cells. MIF-deficient cells exhibit increased resistance transformation. The defects associated with deficiency can be overcome through concomitant inactivation p53 Rb/E2F...