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

• DOI: 10.1038/s41467-017-01845-1
• Publication Date: 2017-11-23T11:28:45Z
• Authors: 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; Magdalena Karbown...
• Keywords: Male; 0301 basic medicine; Lung Neoplasms; Science; Angiomyolipoma; 610; Mice, Transgenic; Mice, SCID; Article; Tuberous Sclerosis Complex 1 Protein; 03 medical and health sciences; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Animals; Humans; Lymphangioleiomyomatosis; Receptor, Notch1; Promoter Regions, Genetic; 0303 health sciences; Tumor Suppressor Proteins; Q; Cell Differentiation; Xenograft Model Antitumor Assays; Neural Crest; Transcription Factor HES-1; Female; Ras Homolog Enriched in Brain Protein

AbstractDifferentiation 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.