Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific ...regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.
PTENα and PTENβ are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. ...Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTENα and PTENβ promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also show that USP9X and FBXW11 bind to the amino-terminal extensions of PTENα/β, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTENα to regulate PTENα/β stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTENα/β. Taken together, our results indicate that the Pten gene is a double-edged sword for carcinogenesis, and reinterpretation of the importance of the Pten gene in carcinogenesis is warranted.
Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we ...show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.
PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and ...accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/β and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/β present opposite effects on carcinogenesis from intracellular PTENα/β, and propose that the tumor-suppressive C-terminal fragment of PTENα/β might be used as exogenous agent to treat cancer.
A endochitinase gene（Tch） from the fungus Trichoderma viride was introduced into broccoli（Brassica oleracea var. italica） by Agrobacterium-mediated transformation. Sixty-eight putative transformants ...were obtained and the presence of the Tch gene was confirmed by both PCR and Southern blot analysis. RT-PCR analysis showed an accumulation of the transcript encoding the endochitinase protein in the transgenic plants. Using real-time quantitative PCR, the expression profiling of endochitinase gene was analyzed. Primary transformants and selfed progeny were examined for expression of the endochitinase using a fluorometric assay and for their resistance to the pathogenic fungi Botrytis cinerea and Rhizoctonia solani. The endochitinase activities in T0 in vitro plants, T0 mature plants and T1 mature plants were correlated with leaf lesions, and the transgenic line T618 had high endochitinse activities of 102.68, 114.53 and 120.27 nmol L–1 MU min–1 mg–1 protein in the three kinds of plants, respectively. The endochitinase activity showed a positive correlation with the resistance to the pathogens. Most transgenic T0 broccoli had increased resistance to the pathogens of B. cinerea and R. solani in leaf assays and this resistance was confirmed to be inheritable. These findings suggested that expression of the Tch gene from T. viride could enhance resistance to pathogenic fungi in Brassica species.
There is an increasingly urgent need of lightweight components in aerospace industry, among which aluminum (Al) alloys have been the optimal materials of choice for aircraft structural parts since ...being used in the Junkers F.13 aircraft in the 1920s. Compared to other metal materials, Al alloys have a lower density, and the use of Al alloys reduces the total weight of the aircraft and improves fuel efficiency and load capacity. Meanwhile, the strength and hardness of Al alloys with alloying and heat treatment can be significantly enhanced for uses in high loads and vibration environments. Furthermore, in the harsh aerospace environment, aircraft may receive various climatic conditions and chemical corrosion. Due to good corrosion and fatigue resistance, Al alloys demonstrate excellent performance under these conditions, ensuring the long–term service life of aircraft. In addition, Al alloys have good recyclability, and they can be recycled to reduce resource consumption and environmental load, in line with the principle of sustainable development. In recent years, although composites have been widely used in aerospace, high–strength Al alloys are still in an indispensable position. Therefore, this article reviews the progress and applications of Al alloys commonly used in aerospace. The common strengthening methods and advanced manufacturing and processing technologies of Al alloy are also discussed, which can provide references for the development of advanced high–performance aviation Al alloys in the future.
Dear Editor, We report a rare case of a mixed germ cell tumor （GCT） that most likely arose from the prostate and included four components： an immature teratoma, a seminoma, an embryonal carcinoma and ...an endodermal sinus tumor （EST）.
Phylogenetic relationships in Rosaceae have long been problematic because of frequent hybridisation, apomixis and presumed rapid radiation, and their historical diversification has not been ...clarified.
With 87 genera representing all subfamilies and tribes of Rosaceae and six of the other eight families of Rosales (outgroups), we analysed 130 newly sequenced plastomes together with 12 from GenBank in an attempt to reconstruct deep relationships and reveal temporal diversification of this family.
Our results highlight the importance of improving sequence alignment and the use of appropriate substitution models in plastid phylogenomics. Three subfamilies and 16 tribes (as previously delimited) were strongly supported as monophyletic, and their relationships were fully resolved and strongly supported at most nodes. Rosaceae were estimated to have originated during the Late Cretaceous with evidence for rapid diversification events during several geological periods. The major lineages rapidly diversified in warm and wet habits during the Late Cretaceous, and the rapid diversification of genera from the early Oligocene onwards occurred in colder and drier environments.
Plastid phylogenomics offers new and important insights into deep phylogenetic relationships and the diversification history of Rosaceae. The robust phylogenetic backbone and time estimates we provide establish a framework for future comparative studies on rosaceous evolution.
The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The ...molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD
levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD
precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD
-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD
levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.
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