The mechanistic Target Of Rapamycin Complex 1 (mTORC1) regulates cellular biosynthetic pathways in response to variations in nutrient availability. Activation of mTORC1 is mediated by Rag GTPases, that act as heterodimers and promote mTORC1 recruitment to the lysosome. Many studies have clarified the post-translational control of mTORC1, but little is known about its transcriptional regulation. Our study demonstrates that TFEB, TFE3 and MITF, members of the MiT/TFE family of transcription factors and master regulators of lysosomal and melanosomal biogenesis and autophagy, are nutrient-sensitive transcriptional activators of mTORC1 signaling. During starvation they induce the expression of the RagD gene and this enhances mTORC1 recruitment to the lysosome and its reactivation when nutrients become available. Thus, in periods of nutrient deprivation, this mechanism allows the cell to rapidly reactivate anabolic pathways and turn off catabolism when nutrient levels are restored. Furthermore this mechanism plays an important role in cancer growth. Up-regulation of the MiT/TFE genes in renal cell carcinoma and melanoma is associated to RagD-induced mTORC1 activation, causing cell hyperproliferation and cancer progression.

ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF MTORC1 ACTIVITY BY MIT/TFE TRANSCRIPTION FACTORS / D. Siciliano ; co-tutor: C. Di Malta ; supervisore interno: C. Settembre; supervisore esterno: M. Pende. - : . DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018. [10.13130/siciliano-diletta_phd2019-01-28].

ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF MTORC1 ACTIVITY BY MIT/TFE TRANSCRIPTION FACTORS

D. Siciliano
2019-01-28

Abstract

The mechanistic Target Of Rapamycin Complex 1 (mTORC1) regulates cellular biosynthetic pathways in response to variations in nutrient availability. Activation of mTORC1 is mediated by Rag GTPases, that act as heterodimers and promote mTORC1 recruitment to the lysosome. Many studies have clarified the post-translational control of mTORC1, but little is known about its transcriptional regulation. Our study demonstrates that TFEB, TFE3 and MITF, members of the MiT/TFE family of transcription factors and master regulators of lysosomal and melanosomal biogenesis and autophagy, are nutrient-sensitive transcriptional activators of mTORC1 signaling. During starvation they induce the expression of the RagD gene and this enhances mTORC1 recruitment to the lysosome and its reactivation when nutrients become available. Thus, in periods of nutrient deprivation, this mechanism allows the cell to rapidly reactivate anabolic pathways and turn off catabolism when nutrient levels are restored. Furthermore this mechanism plays an important role in cancer growth. Up-regulation of the MiT/TFE genes in renal cell carcinoma and melanoma is associated to RagD-induced mTORC1 activation, causing cell hyperproliferation and cancer progression.
BALLABIO, ANDREA
TFEB; mTORC1; amino acids; Rag-GTPases
Settore BIO/18 - Genetica
ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF MTORC1 ACTIVITY BY MIT/TFE TRANSCRIPTION FACTORS / D. Siciliano ; co-tutor: C. Di Malta ; supervisore interno: C. Settembre; supervisore esterno: M. Pende. - : . DIPARTIMENTO DI ONCOLOGIA ED EMATO-ONCOLOGIA, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018. [10.13130/siciliano-diletta_phd2019-01-28].
Doctoral Thesis
File in questo prodotto:
File Dimensione Formato  
phd_unimi_R11146.pdf

accesso aperto

Tipologia: Tesi di dottorato completa
Dimensione 109.16 MB
Formato Adobe PDF
109.16 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/607642
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact