Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/139728
Title: METABOLIC REGULATION OF HIF-1a AND mTORC1 SIGNALLING
Authors: CHOW AI LEE
Keywords: HIF-1a, pyruvate, ammonia, mTORC1, asparagine, hepatocellular carcinoma
Issue Date: 12-Feb-2018
Source: CHOW AI LEE (2018-02-12). METABOLIC REGULATION OF HIF-1a AND mTORC1 SIGNALLING. ScholarBank@NUS Repository.
Abstract: Metabolic dysregulation and hyperactivation of oncogenic pathways are hallmarks of oncogenesis often studied as parallel events. Yet, emerging evidences suggest that oncometabolites do crosstalk with oncogenes. I first investigated the link between end-product of glycolysis, pyruvate and the expression of hypoxia inducible factor-1α (HIF-1α), master regulator of glycolytic pathways. I proposed that localisation of α-ketoglutarate (relative to prolyl hydroxylases) and maintenance of TCA cycle homeostasis regulate pyruvate-induced HIF-1α stabilisation at normoxia. Serendipitous observations subsequently identified ammonium ions (NH4+) capable of sensitising mammalian target of rapamycin complex 1 (mTORC1) to amino acids in a Src/Akt-dependent manner. I next described how amidic amino acids, glutamine and asparagine regulate mTORC1, because their aggressive catabolism has been linked to hyperammonaemia in tumours’ milieu. I observed that the amides’ intracellular accumulation preceded exchange for extracellular essential amino acids to in turn activate mTORC1, and mediated detection of endogenous amino acids in an Arf1-dependent manner.
URI: http://scholarbank.nus.edu.sg/handle/10635/139728
Appears in Collections:Ph.D Theses (Open)

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