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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Giannik, 2017. "Notch transactivates Rheb to maintain the multipotency of TSC-null cells," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01845-1
    DOI: 10.1038/s41467-017-01845-1
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    Cited by:

    1. J. O. R. Hernandez & X. Wang & M. Vazquez-Segoviano & M. Lopez-Marfil & M. F. Sobral-Reyes & A. Moran-Horowich & M. Sundberg & D. O. Lopez-Cantu & C. K. Probst & G. U. Ruiz-Esparza & K. Giannikou & R., 2021. "A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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