First Author | Cho JH | Year | 2017 |
Journal | Nat Commun | Volume | 8 |
Issue | 1 | Pages | 1848 |
PubMed ID | 29184052 | Mgi Jnum | J:255870 |
Mgi Id | MGI:6106380 | Doi | 10.1038/s41467-017-01845-1 |
Citation | Cho JH, et al. (2017) Notch transactivates Rheb to maintain the multipotency of TSC-null cells. Nat Commun 8(1):1848 |
abstractText | Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma. |