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Cho JH, Patel B, Bonala S, Manne S, Zhou Y, Vadrevu SK, Patel J, Peronaci M, Ghouse S, Henske EP, Roegiers F, Giannikou K, Kwiatkowski DJ, Mansouri H, Markiewski MM, White B, Karbowniczek M
Notch transactivates Rheb to maintain the multipotency of TSC-null cells
Nat Commun (2017) 8:1848.
Abstract
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.
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Publication Date: 2017-11-29.
PMCID: PMC5705704
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