Notch transactivates Rheb to maintain the multipotency of TSC-null cells

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 lymphangiol...

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Published in:Nature communications 2017-11, Vol.8 (1), p.1848-16, Article 1848
Main Authors: Cho, Jun-Hung, Patel, Bhaumik, Bonala, Santosh, Manne, Sasikanth, Zhou, Yan, Vadrevu, Surya K., Patel, Jalpa, Peronaci, Marco, Ghouse, Shanawaz, Henske, Elizabeth P., Roegiers, Fabrice, Giannikou, Krinio, Kwiatkowski, David J., Mansouri, Hossein, Markiewski, Maciej M., White, Brandon, Karbowniczek, Magdalena
Format: Article
Language:English
Subjects:
631/67
631/67/1244
Abnormalities
Angiomyolipoma
Animal models
Binding
Cell culture
Cell differentiation
Cysts
Differentiation (biology)
Humanities and Social Sciences
Invasiveness
Kidney cancer
multidisciplinary
Nestin
Notch1 protein
Null cells
Renal cell carcinoma
Rodents
Science
Science (multidisciplinary)
Tuberous sclerosis
Tuberous Sclerosis Complex 1
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Summary: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. Tuberous sclerosis complex (TSC) is a rare genetic condition causing tumours with differentiation abnormalities; however the molecular mechanisms causing these defects are unclear. Here the authors show that Notch cooperates with Rheb to block cell differentiation forming a regulatory loop that could underlie TSC tumorigenesis.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-01845-1