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

Jun-Hung Cho, Bhaumik Patel, Santosh Bonala, Sasikanth Manne, Yan Zhou, Surya K. Vadrevu, Jalpa Patel, Marco Peronaci, Shanawaz Ghouse, Elizabeth P. Henske, Fabrice Roegiers, Krinio Giannikou, David J. Kwiatkowski, Hossein Mansouri, Maciej M. Markiewski, Brandon White () and Magdalena Karbowniczek ()
Additional contact information
Jun-Hung Cho: Texas Tech University Health Science Center
Bhaumik Patel: Texas Tech University Health Science Center
Santosh Bonala: Texas Tech University Health Science Center
Sasikanth Manne: Texas Tech University Health Science Center
Yan Zhou: Fox Chase Cancer Center
Surya K. Vadrevu: Texas Tech University Health Science Center
Jalpa Patel: Texas Tech University Health Science Center
Marco Peronaci: Texas Tech University Health Science Center
Shanawaz Ghouse: Texas Tech University Health Science Center
Elizabeth P. Henske: Brigham and Women’s Hospital and Harvard Medical School
Fabrice Roegiers: Fox Chase Cancer Center
Krinio Giannikou: Harvard Medical School and Dana Farber Cancer Institute
David J. Kwiatkowski: Harvard Medical School and Dana Farber Cancer Institute
Hossein Mansouri: Texas Tech University
Maciej M. Markiewski: Texas Tech University Health Science Center
Brandon White: San Jose State University
Magdalena Karbowniczek: Texas Tech University Health Science Center

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01845-1

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