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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Angiomyolipoma / metabolism
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Angiomyolipoma / pathology*
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Female
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Humans
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Lymphangioleiomyomatosis / metabolism
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Lymphangioleiomyomatosis / pathology*
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Male
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Mice, SCID
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Mice, Transgenic
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Neural Crest / metabolism
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Neural Crest / pathology
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Promoter Regions, Genetic
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Ras Homolog Enriched in Brain Protein / genetics
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Ras Homolog Enriched in Brain Protein / metabolism*
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Transcription Factor HES-1 / genetics
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Transcription Factor HES-1 / metabolism
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Tuberous Sclerosis / metabolism
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / genetics
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Xenograft Model Antitumor Assays
Substances
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NOTCH1 protein, human
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RHEB protein, human
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Ras Homolog Enriched in Brain Protein
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Receptor, Notch1
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TSC1 protein, human
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Transcription Factor HES-1
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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HES1 protein, human