DDIT4
Description
The DDIT4 (DNA damage inducible transcript 4) is a protein-coding gene located on chromosome 10.
DNA-damage-inducible transcript 4 (DDIT4) protein, also known as protein regulated in development and DNA damage response 1 (REDD1), is a protein that in humans is encoded by the DDIT4 gene. DDIT4 acts as a negative regulator of mTOR, a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy. In particular, upregulation of HIF-1 in response to hypoxia upregulates DDIT4, leading to activation of Tsc1/2 via 14–3–3 shuttling and subsequent downregulation of mTOR via Rheb. In addition to hypoxia, DDIT4 expression has also been shown to be activated by DNA damage and energy stress. Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging and linked with diseases such as tuberous sclerosis, lymphangioleiomyomatosis, diabetes, and cancer. In particular, the overactivation of mTOR in many cancer types has led to the development of mTOR inhibitors for cancer treatment. DDIT4 has begun to receive attention in this regard via the diabetes drug Metformin which has been shown to reduce cancer risk and increase DDIT4 expression.
DDIT4 regulates cell growth, proliferation and survival by inhibiting the activity of the mammalian target of rapamycin complex 1 (mTORC1). This inhibition is mediated through a pathway involving DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. DDIT4 plays a key role in responding to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. It regulates p53/TP53-mediated apoptosis in response to DNA damage by affecting mTORC1 activity. The role of DDIT4 in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes. DDIT4 is required for mTORC1-mediated defense against viral protein synthesis and virus replication. It inhibits neuronal differentiation and neurite outgrowth mediated by NGF through its effect on mTORC1 activity. DDIT4 is required for normal neuron migration during embryonic brain development and plays a role in neuronal cell death.
DDIT4 is also known as Dig2, REDD-1, REDD1.
