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Notch transactivates Rheb to maintain the multipotency of TSC-null cells.
- Source :
-
Nature communications [Nat Commun] 2017 Nov 29; Vol. 8 (1), pp. 1848. Date of Electronic Publication: 2017 Nov 29. - Publication Year :
- 2017
-
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.
- Subjects :
- Angiomyolipoma metabolism
Animals
Cell Differentiation genetics
Cell Differentiation physiology
Female
Humans
Lung Neoplasms metabolism
Lymphangioleiomyomatosis metabolism
Male
Mice, SCID
Mice, Transgenic
Neural Crest metabolism
Neural Crest pathology
Promoter Regions, Genetic
Ras Homolog Enriched in Brain Protein genetics
Receptor, Notch1 genetics
Transcription Factor HES-1 genetics
Transcription Factor HES-1 metabolism
Tuberous Sclerosis metabolism
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins genetics
Xenograft Model Antitumor Assays
Angiomyolipoma pathology
Lung Neoplasms pathology
Lymphangioleiomyomatosis pathology
Ras Homolog Enriched in Brain Protein metabolism
Receptor, Notch1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 29184052
- Full Text :
- https://doi.org/10.1038/s41467-017-01845-1