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mTOR activity under hypoxia
Douangsone D Vadysirisack1, Leif W Ellisen
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
Abstract:
The adaptive response to hypoxia, low oxygen tension, involves inhibition of energy-intensive cellular processes including protein translation. This effect is mediated in part through a decrease in the kinase activity of mammalian target of rapamycin complex 1 (mTORC1), a master regulator of protein translation. The principle mechanism for hypoxia-induced mTORC1 inhibition, however, was not elucidated until recently. Our work has demonstrated that the stress-induced protein REDD1 is essential for hypoxia regulation of mTORC1 activity and has further defined the molecular mechanism whereby REDD1 represses mTORC1 activity under hypoxic stress. Using our studies with REDD1 as an example, we describe in detail biochemical approaches to assess mTORC1 activity in the hypoxic response. Here, we provide methodologies to monitor signaling components both downstream and upstream of the hypoxia-induced mTORC1 inhibitory pathway. These methodologies will serve as valuable tools for researchers seeking to understand mTORC1 dysregulation in the context of hypoxic stress.
Insights
Hypoxia, or low oxygen, inhibits protein translation by decreasing mammalian target of rapamycin complex 1 (mTORC1) activity. The protein REDD1 is essential for this hypoxia-induced mTORC1 inhibition, with detailed molecular mechanisms now elucidated.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Hypoxia triggers adaptive cellular responses, including the inhibition of energy-intensive processes like protein translation.
- Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of protein translation, and its activity decreases during hypoxia.
- The precise molecular mechanisms underlying hypoxia-induced mTORC1 inhibition were not fully understood.
Purpose of the Study:
- To elucidate the role of the stress-induced protein REDD1 in hypoxia-mediated mTORC1 inhibition.
- To define the molecular mechanism by which REDD1 represses mTORC1 activity under hypoxic conditions.
- To provide biochemical methodologies for assessing mTORC1 activity and related signaling pathways in hypoxic stress.
Main Methods:
- Biochemical assays to measure kinase activity of mTORC1.
- Western blotting to monitor signaling components upstream and downstream of mTORC1.
- Cellular studies using REDD1 as a model system to investigate hypoxic stress response.
Main Results:
- Demonstrated that the stress-induced protein REDD1 is essential for regulating mTORC1 activity during hypoxia.
- Elucidated the molecular mechanism through which REDD1 represses mTORC1 activity under hypoxic stress.
- Established methodologies to assess mTORC1 signaling in the context of hypoxic stress.
Conclusions:
- REDD1 plays a critical role in the adaptive response to hypoxia by inhibiting mTORC1.
- Understanding the REDD1-mTORC1 axis provides insight into cellular adaptation to low oxygen.
- The described biochemical methods are valuable tools for studying mTORC1 dysregulation in hypoxic conditions.
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