Rabbit Anti-Human TSC2 Polyclonal Antibody

Tuberous sclerosis complex is a dominantly inherited genetic disorder of striking clinical variability. It is caused by mutations in either TSC1 or TSC2 gene, which regulate cell growth and proliferation by inhibition of mTORC1 signaling. TS is characterized by the development of benign tumors in many tissues and organs and its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. With mechanism-based mTOR inhibitors therapy now available for many of its manifestations, early diagnosis of TSC is very important in order to offer appropriate care, long-term surveillance and parental counseling. Fetal ultrasound and MRI imaging techniques have evolved and may capture even earlier the following TSC-associated lesions: cardiac rhabdomyomas, subependymal nodules, cortical tubers and renal cysts. Often these represent an incidental finding during a routine ultrasound. Furthermore, in the past decades prenatal molecular diagnosis of TSC has emerged as an important option for families with a known affected member; however, the existing evidence with regards to the clinical characteristics and long-term outcome of babies diagnosed prenatally with TSC is yet limited and the path that follows early TSC detection merits further research. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

miR-29b has been identified as a rapamycin-induced microRNA (miRNA) in Tsc2-deficient, mTORC1-hyperactive cells. The biological significance of this induction of miR-29b is unknown. We have found that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed cell proliferation, anchorage-independent cell growth, cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo. Importantly, the combination of miR-29b inhibition with rapamycin treatment further inhibited these tumor-associated cellular processes. To gain insight into the molecular mechanisms by which miR-29b promotes tumorigenesis, we used RNA sequencing to identify the tumor suppressor retinoid receptor beta (RAR beta) as a target gene of miR-29b. We found that miR-29b directly targeted the 3'UTR of RAR beta. Forced expression of RAR beta reversed the effects of miR-29b overexpression in proliferation, migration, and invasion, indicating that it is a critical target. miR-29b expression correlated with low RAR beta expression in renal clear cell carcinomas and bladder urothelial carcinomas, tumors associated with TSC gene mutations. We further identified growth family member 4 (ING4) as a novel interacting partner of RAR beta. Overexpression of ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed the RAR beta-mediated suppression of cell migration and invasion. Taken together, our findings reveal a novel miR-29b/RAR beta/ING4 pathway that regulates tumorigenic properties of Tsc2-deficient cells, and that may serve as a potential therapeutic target for TSC, lymphangioleiomyomatosis (LAM), and other mTORC1-hyperactive tumors.