Search

Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten−/−Ptpn1−/− mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate prostate cancer, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten−/− mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer. Cancer Res; 76(11); 3130–5. ©2016 AACR.

Bcl-2 associated factor 1 (Bclaf1) is a nuclear protein that was originally identified in a screen of proteins that interact with the adenoviral bcl-2 homolog E1B19K. Overexpression of Bclaf1 was shown to result in apoptosis and transcriptional repression that was reversible in the presence of Bcl-2 or Bcl-x(L). Furthermore, antiapoptotic members, but not proapoptotic members of the Bcl-2 protein family, were shown to interact with Bclaf1 and prevent its localization to the nucleus. Bclaf1 has also recently been identified as a binding partner for Emerin, a nuclear membrane protein that is mutated in X-linked recessive Emery-Dreifuss muscular dystrophy. To ascertain the in vivo function of Bclaf1, we have generated mice that carry a targeted mutation of the bclaf1 locus. In this study, we show that Bclaf1 is required for proper spatial and temporal organization of smooth muscle lineage during the saccular stage of lung development. We also show that Bclaf1 is dispensable for thymocyte development but is essential for peripheral T-cell homeostasis. Despite its postulated role as a proapoptotic protein, Bclaf1-deficient cells did not show any defect in cell death linked to development or after exposure to various apoptotic stimuli. Our findings show a critical role for Bclaf1 in developmental processes independent of apoptosis.

The Drosophila melanogaster warts/lats tumour suppressor has two mammalian counterparts LATS1/Warts-1 and LATS2/Kpm. Here, we show that mammalian Lats orthologues exhibit distinct expression profiles according to germ cell layer origin. Lats2(-/-) embryos show overgrowth in restricted tissues of mesodermal lineage; however, lethality ultimately ensues on or before embryonic day 12.5 preceded by defective proliferation. Lats2(-/-) mouse embryonic fibroblasts (MEFs) acquire growth advantages and display a profound defect in contact inhibition of growth, yet exhibit defective cytokinesis. Lats2(-/-) embryos and MEFs display centrosome amplification and genomic instability. Lats2 localizes to centrosomes and overexpression of Lats2 suppresses centrosome overduplication induced in wild-type MEFs and reverses centrosome amplification inherent in Lats2(-/-) MEFs. These findings indicate an essential role of Lats2 in the integrity of processes that govern centrosome duplication, maintenance of mitotic fidelity and genomic stability.

Mus81-Eme1 endonuclease has been implicated in the rescue of stalled replication forks and the resolution of meiotic recombination intermediates in yeast. We used gene targeting to study the physiological requirements of Mus81 in mammals. Mus81 –/– mice are viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA cross-linking agent mitomycin C but not to γ-irradiation. Remarkably, both homozygous Mus81 –/– and heterozygous Mus81 +/– mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.

Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans. The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption ofcaspase 8is lethal in utero. We generated mice with a targetedcaspase 8mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli.caspase 8ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria.caspase 8mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency.