DEDD

Official Full Name

death effector domain containing

Organism

Homo sapiens

GeneID

9191

Background

This gene encodes a protein that contains a death effector domain (DED). DED is a protein-protein interaction domain shared by adaptors, regulators and executors of the programmed cell death pathway. Overexpression of this gene was shown to induce weak apoptosis. Upon stimulation, this protein was found to translocate from cytoplasm to nucleus and colocalize with UBTF, a basal factor required for RNA polymerase I transcription, in the nucleolus. At least three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

DEFT; KE05; DEDD1; FLDED1; DEDPro1; FLDED-1; CASP8IP1;

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Detailed Information

Death effector domains (DEDs) are protein-protein interaction structures found in proteins that modulate a variety of signaling pathways.DEDs are part of a large family of death effector structures that are primarily used to control programmed cell death. The seven canonical DED-containing proteins are the fas-associated death domain proteins (FADD), Caspase-8 and 10, cellular FLICE-like inhibitory proteins (c-FLIP), DNA-binding death effector domain-containing proteins (DEDD), DEDD2, and phosphoepitin 15-Kda (PEA-15), which is enriched in astrocytes. These proteins are particularly implicated in the regulation of apoptosis and proliferation mediated by the tumor necrosis factor alpha (TNFalpha) receptor family. DED-containing proteins regulate transcription, migration and proliferation in addition to their pro- and anti-apoptotic functions. In particular, DED proteins are essential in embryonic development and immune system homeostasis.

Structure and Function of Dedd

The Dedd gene is located on chromosome 19p13.3 and spans approximately 12 kb. It encodes a protein of 419 amino acids, which is characterized by the presence of a death effector domain (DED). This domain is involved in the regulation of apoptosis by facilitating the recruitment of caspases, the executioners of apoptosis. Dedd is primarily expressed in the cytoplasm and nucleus of cells, where it plays a crucial role in the regulation of cell survival and death.

Dedd interacts with various apoptosis signaling molecules, such as tumor necrosis factor (TNF) receptors, Fas, and Bcl-2 family proteins. These interactions enable Dedd to modulate the activity of caspases, thereby controlling the onset and progression of apoptosis. Additionally, Dedd has been shown to interact with transcription factors, such as p53 and nuclear factor kappa B (NF-κB), suggesting a role for Dedd in the regulation of gene expression during apoptosis.

Figure 1. Proposed model of the roles of death effector domain-containing DNA-binding protein (DEDD) and combinatorial treatment mechanism in triple-negative breast cancer (TNBC).

Autophagy of Dedd

Metastasis is the spread of cancer cells from the primary site to other parts of the body. Metastatic cancer is the cause of most cancer deaths. A key developmental program, epithelial-mesenchymal transition (EMT), helps control cancer invasion and metastasis. Death effector domain-containing DNA-binding protein (DEDD), which is a key effector molecule of cell death signaling receptors, attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that DEDD physically interacts with a class III PtdIns 3-kinase complex containing PIK3C3 and BECN1, which control key aspects of autophagy; this interaction activates autophagy and induces autophagy-mediated lysosomal degradation of SNAI/Snail and TWIST, which are Snail and TWIST are two major inducers of the EMT process. Further studies revealed that the interaction of DEDD with PIK3C3 supports the stability of PIK3C3, which maintains autophagic activity and promotes the degradation of SNAI and TWIST. Our findings suggest that DEDD is a prognostic marker and a potential therapeutic target for the prevention and treatment of cancer metastasis. Furthermore, modulation of DEDD-PIK3C3 interactions may be an entry point for translating modulators of this interaction into clinical endpoints.

References

Ni Y, Schmidt KR, Werner BA, et al. Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer. Nat Commun. 2019;10(1):2860. Published 2019 Jun 28. doi:10.1038/s41467-019-10743-7
Zhan Y, Hegde R, Srinivasula SM, Fernandes-Alnemri T, Alnemri ES. Death effector domain-containing proteins DEDD and FLAME-3 form nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC. Cell Death Differ. 2002;9(4):439-447. doi:10.1038/sj.cdd.4401038

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