Inhibitor of Apoptosis Proteins (IAPs) can bind to and inhibit caspases, the key executioners of apoptosis. Because IAPs are frequently overexpressed in human tumors, they have become major pharmacological targets for developing new cancer therapeutics. However, the precise physiological function of individual mammalian IAPs and their role as E3 ubiquitin-ligases in situ remain largely obscure. Here, we investigated the function of XIAP ubiquitin-ligase activity by inactivating the RING motif via gene targeting in the mouse. Removing the RING stabilized XIAP in apoptotic thymocytes, demonstrating that XIAP ubiquitin-ligase activity is a major determinant of XIAP protein stability. Surprisingly, the increased amounts of "XIAP-BIR-only" protein did not lead to attenuated but rather increased caspase activity and apoptosis. ⌬RING embryonic stem cells and fibroblasts had elevated caspase-3 enzyme activity, and XIAP ⌬RING embryonic fibroblasts were strongly sensitized to TNF-␣-induced apoptosis. Similar results were obtained with XIAP deficient mice. Furthermore, deletion of the RING also improved the survival of mice in the Eµ-Myc lymphoma model. This demonstrates a physiological requirement of XIAP ubiquitin-ligase activity for the inhibition of caspases and for tumor suppression in vivo.[Keywords: XIAP; ubiquitin; caspase; apoptosis; cancer; lymphoma] Supplemental material is available at http://www.genesdev.org.

Inhibitor of Apoptosis Proteins (IAPs) are frequently overexpressed in tumors and have become promising targets for developing anti-cancer drugs. IAPs can be inhibited by natural antagonists, but a physiological requirement of mammalian IAP antagonists remains to be established. Here we show that deletion of the mouse Sept4 gene, which encodes the IAP antagonist ARTS, promotes tumor development. Sept4-null mice have increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Em-Myc background. These phenotypes are partially suppressed by inactivation of XIAP. Our results suggest that apoptosis plays an important role as a frontline defense against cancer by restricting the number of normal stem cells.[Keywords: Apoptosis; cancer; tumor suppressor; IAP; stem cells; lymphoma] Supplemental material is available at http://www.genesdev.org.

This review compares two novel polygenic mouse models of type 2 diabetes (T2D), TALLYHO/JngJ and NONcNZO10/LtJ, and contrasts both with the well-known C57BLKS/J-Leprdb (db/db) monogenic diabesity model. We posit that the new polygenic models are more representative of the “garden variety” obesity underlying human T2D in terms of their polygenetic rather than monogenic etiology. Moreover, the clinical phenotypes in these new models are less extreme, for example, more moderated development of obesity coupled with less extreme endocrine disturbances. The more progressive development of obesity produces a maturity-onset development of hyperglycemia in contrast to the juvenile-onset diabetes observed in the morbidly obese db/db model. Unlike the leptin receptor-deficient db/db models with central leptin resistance, the new models develop a progressive peripheral leptin resistance and are able to maintain reproductive function. Although the T2D pathophysiology in both TALLYHO/JngJ and NONcNZO10/LtJ is remarkably similar, their genetic etiologies are clearly different, underscoring the genetic heterogeneity underlying T2D in humans.

Type 1 diabetes (T1D) is characterized by a partial or total insufficiency of insulin. The premiere animal model of autoimmune T cell-mediated T1D is the NOD mouse. A dominant negative mutation in the mouse insulin 2 gene (Ins2Akita) produces a severe insulin deficiency syndrome without autoimmune involvement, as do a variety of transgenes overexpressed in beta cells. Pharmacologically-induced T1D (without autoimmunity) elicted by alloxan or streptozotocin at high doses can generate hyperglycemia in almost any strain of mouse by direct toxicity. Multiple low doses of streptozotocin combine direct beta cell toxicity with local inflammation to elicit T1D in a male sex-specific fashion. A summary of protocols relevant to the management of these different mouse models will be covered in this overview.

Aging is a complex dynamic process that leads to increased susceptibility to various diseases including cancer. Immunosenescence is a state of aging-related gradual deterioration of the immune system in the elderly. T cells are a major part of an adaptive immune system and orchestrate the cellular immune response. However, only limited studies were conducted on how aging, immunosenescence, and cancer therapy affect each other. Our goals in this study were to establish a mouse model that shows immunosenescence and to study how the immunosenescence affects checkpoint inhibitor efficacy in a C57BL/6J syngeneic model. Young (7 weeks of age), mid-aged (54 weeks) and aged (76–78 weeks) female mice were used. The spleen and blood were collected from the naïve mice and analyzed using a flow cytometer. In both samples, we found a decrease in naïve CD4+ and CD8+ T cells in mid-aged and aged mice compared to the young counterparts, which is a sign of immunosenescence. Compared to young mice naïve aged mice showed increased regulatory T cells (Tregs) in the spleen without a significant difference in the blood. When the mice were inoculated with MC38 tumors and treated with isotype control or anti-PD1 antibody for 3 weeks, anti-PD1 treatment was found to significantly slow down tumor growth in all age groups but was the most efficacious in aged mice. Anti-PD1 treatment increased T cell infiltration into the tumor with the greatest effect observed in the mid-aged group. In conclusion, we have established a preclinical mouse model that shows immunosenescence, and immunosenescence is a possible cause of the difference in response to the checkpoint inhibitor in the elderly.