Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease or peripheral neurofibromatosis, is a common autosomal dominant disorder characterised by multiple neurofibromas, cafe au lait spots, and Lisch nodules of the iris, with a variable clinical expression. The gene responsible for this condition, NF1, has been isolated by positional cloning. It spans over 350kb of genomic DNA in chromosomal region 17qll.2 and encodes an mRNA of 11-13 kb containing at least 59 exons. NFI is widely expressed in a variety of human and rat tissues. Four alternatively spliced NFI transcripts have been identified. Three of these transcript isoforms (each with an extra exon: 9br, 23a, and 48a, respectively) show differential expression to some extent in various tissues, while the fourth isoform (2-9kb in length) remains to be examined. The protein encoded by NFI, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. The identification of somatic mutations in NFI from tumour tissues strongly supports the speculation that NFl is a member of the tumour suppressor gene family. Although the search for mutations in the gene has proved difficult, germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. Further extensive studies are required to elucidate the gene function and the mutation spectrum. This should then facilitate the molecular diagnosis and the development of new therapy for the disease.
Recent clinical trials using rapalogues in tuberous sclerosis complex (TSC) show regression in volume of typically vascularised tumours including angiomyolipomas (AMLs) and sub-ependymal giant cell astrocytomas (SEGAs). By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur in part through suppression of hypoxia inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1α protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/− mouse model. We establish that mTORC1 drives HIF-1α protein accumulation through enhanced transcription of HIF-1α mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrate that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whilst HIF-1α degradation remains unaffected. We therefore propose that mTORC1 drives HIF-1α synthesis in a multi-faceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observe a disconnect between HIF-1α protein levels and VEGF-A expression. While both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.
Background: Granulosa cell (GC) apoptosis is the main cause of follicular atresia, and oxidative stress is involved in this process. Results: GC apoptosis is caused by FoxO1 activity in oxidative stress. Conclusion: FoxO1 is critical in oxidative stress-induced GC apoptosis. Significance: Our results detail the mechanism of follicular atresia and indicate that FoxO1 is a potential target in preventing follicular atresia from oxidative stress.
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