Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ −/− tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ −/− MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.casein kinase 1 | PA28γ P remature aging refers to unusual acceleration of the natural aging process and is induced by multiple factors such as genetics, environment, and stress conditions. Many biological markers of premature aging have been described over the past century, including blindness, gray/yellow hair, ear atrophy, osteoporosis, lordokyphosis of the spine, reduced hair regrowth, delayed wound healing, and a shortened lifespan (1, 2). Recently, progress has been made in understanding some of the mechanisms of premature aging (3, 4). DNA damage, oxidative stress, and mitochondrial DNA (mtDNA) mutations are associated with premature aging and may be contributing agents. Furthermore, abnormalities in several cancer-related proteins such as cyclin-dependent kinase inhibitor 1 (p21), tumor protein 53 (p53), and E2F family of transcription factors (retinoblastoma-associated protein; E2F1) also are known to cause premature aging phenotypes (5-8). Given that longer lifespan is mostly associated with an increased cancer incidence, maintaining the balance between longevity and reduced risk of cancer remains a formidable task.Discrepancies between proaging and antiaging effects of p53 were observed in different experimental systems. A p53 hypermorphic mouse model that harbored a mutant p53 allele (m-p53) displayed resistance to spontaneous cancers, a shortened lifespan, and premature aging phenotypes (2). The role of p53 in promoting aging is supported by a different mouse model, in which a 44-kDa truncated naturally occurring isoform of p53 (p44 +/+ ) is expressed (7). The p44 +/+ mice displayed enhanced p53 activity and phenot...

It has been reported that the proteasome activator REGγ is associated with multiple oncogenic pathways in human cancers. However, the role of REGγ in the development of melanoma and the underlying mechanisms remain unclear. In this study, we attempted to investigate the effects of REGγ on human melanoma cell proliferation in vitro and in vivo. We demonstrated that knockdown of REGγ inhibited melanoma cell growth and arrested melanoma cell at G1 phase. Furthermore, depletion of REGγ also inhibited the xenograft growth of human melanoma. Mechanistically, REGγ activates Wnt/β-catenin signal pathway by degrading GSK-3β in melanoma cell lines and mouse models. Transient knockdown of β-catenin effectively blocked cell proliferation in REGγ wild-type melanoma cells. In human melanoma samples, REGγ was overexpressed and positively correlated with β-catenin levels. This study demonstrates that REGγ is a central molecule in the development of melanoma by regulating Wnt/β-catenin pathway. This suggests that targeting REGγ could be an alternative therapeutic approach for melanoma.

The effect of increasing levels of dietary de‐oiled soybean lecithin (SL) on the ovarian development of female redclaw crayfish, Cherax quadricarinatus, was investigated. Five practical formulated diets were supplemented with 0% (Diet 1), 1% (Diet 2), 2% (Diet 3), 4% (Diet 4) and 6% (Diet 5) SL. Crayfish (initial weight: 25.64 ± 1.53 g) were fed each diet in four replicates for 8 weeks. Crayfish that were fed diets containing ≥2% SL had a significantly higher gonadosomatic index than those fed with Diets 1 and 2 (P < 0.05), while hepatosomatic index showed a decreasing trend (P > 0.05). The fatty acid composition of the hepatopancreas is largely due to the dietary composition. Higher dietary SL yielded a higher percentage of ovarian polyunsaturated and highly unsaturated fatty acids (P < 0.05). Furthermore, the higher content of linoleic acid and alpha linolenic acid in diets may be more important for ovarian development in C. quadricarinatus, as these originate from the hepatopancreas. The hepatopancreatic vitellogenin mRNA expression was the highest in crayfish that received Diet 3. Our results suggest that dietary SL has a positive effect on ovarian development in C. quadricarinatus broodstock, and at least 2% SL should be supplemented in broodstock diets to enhance ovarian maturation during aquaculture.

Cancer stem cells are responsible for tumorigenesis, progression, recurrence and metastasis. Intestinal stem cells (ISCs) are regarded as the origin of intestinal neoplasia. Inflammation also serves an important role in intestinal neoplasia. To explore the molecular mechanisms underlying the inflammation-mediated induction of intestinal tumorigenesis, the present study investigated the function of tumor necrosis factor (TNF)-α in the malignant transformation of ISCs. NCM460 spheroid (NCM460s) cells with higher expression of stem cell genes, such as Oct4, Nanog, Sox2 and Lgr5, and with a higher ratio of CD133 + , were obtained from NCM460 cells in serum-free medium. TNF-α accelerated cell proliferation, migration and invasion, induced chemotherapy resistance and the epithelial-mesenchymal transition. NF-κB and Wnt/β-catenin pathways were activated in TNF-α-induced inflammatory responses, leading to the nuclear translocation of p65 and β-catenin, as well as promoter activity of NF-κB and TCF/LEF transcription factors. It was further demonstrated that TNF-α-induced activation of the NF-κB and Wnt/β-catenin signaling pathways, as well as the upregulation of proinflammatory cytokines, were significantly suppressed by p65-knockdown. Notably, PDTC, an inhibitor of NF-κB signaling, reversed TNF-α-induced activation of the NF-κB and Wnt/β-catenin pathways. A similar role was observed for IWP-2, an inhibitor of Wnt/β-catenin signaling. Collectively, these results demonstrated that the NF-κB and Wnt/β-catenin pathways were activated to promote TNF-α-induced malignant transformation of ISCs, in which these two pathways cross-regulated each other.

No abstract