FADD

Official Full Name

Fas associated via death domain

Organism

Homo sapiens

GeneID

8772

Background

The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be recruited by TNFRSF6/Fas-receptor, tumor necrosis factor receptor, TNFRSF25, and TNFSF10/TRAIL-receptor, and thus it participates in the death signaling initiated by these receptors. Interaction of this protein with the receptors unmasks the N-terminal effector domain of this protein, which allows it to recruit caspase-8, and thereby activate the cysteine protease cascade. Knockout studies in mice also suggest the importance of this protein in early T cell development. [provided by RefSeq, Jul 2008]

Synonyms

GIG3; IMD90; MORT1;

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Detailed Information

Fas-associated death domain-containing protein (FADD) is the key adaptor protein transmitting apoptotic signals, which is mediated by death receptors. Except for its key role in death receptor signaling of apoptosis, FADD also takes part in embryonic development, cell cycle progression, lymphocyte proliferation and activation, innate immunity and chemosensitization. Previous researchers have found that these non-apoptotic activities of FADD are partially because of its phosphorylation (serine 191 in mouse and serine 194 in human), which is at the C-terminal tail of FADD outside apoptotic domains and is adjusted dependent on the cell cycle. Mice bearing the mutation mimicking constitutive phosphorylation (S191D) of FADD are immunodeficiency, similar to FADD-deficient mice. FADD is located on chromosome 11q13.3, which is a diabetes susceptibility locus; therefore, it has been suspected that alterations in FADD might induce diabetes. Additionally, during the last decade, FADD has been found to play a critical role in most of the signalosome complexes, such as the inflammasome and the necroptosome. Interestingly, multitudinous mechanisms involved in regulating FADD functions have been identified, essentially posttranslational modifications and secretion.

However, FADD implication in cancer is complicated, due to pleiotropic effects. It has been reported either as anti- or protumorigenic, depending on the cellular type.

FADD in pancreatic cancer

As a proapoptotic protein, FADD functions as a tumor inhibitor in some types of cancer, including thyroid adenoma/adenocarcinoma and thymic lymphoblastic lymphoma. Low level of FADD has also been detected in the leukemic cells of acute myeloid leukemia patients. To the contrary, FADD is up-regulation in certain types of cancer. FADD is located on chromosome 11q13, a region that is frequently amplified in certain types of cancer, including head and neck squamous cell carcinoma, lung, laryngeal and pharyngeal carcinomas, and breast and ovarian carcinomas. FADD mRNA and protein levels are increased in these forms of cancer. However, the role of FADD in these diseases remains elucidated. Pancreatic cancer is one of the most mortal types of cancer worldwide and the early stages are difficult to diagnose, thus hampering prompt chemotherapy, surgery and radiotherapy. Besides, pancreatic cancer is not sensitive to traditional chemotherapy and radiotherapy, which is principally due to failure of inducing cell apoptosis and cycle arrest in pancreatic cancer cells. FADD is up-regulation in pancreatic cancer cells. Furthermore, its expression is correlative with pancreatic cancer cell drug resistance. FADD RNA interference caused increased cell cycle arrest and apoptosis in response to Adriamycin® treatment in drug-resistant cells. The present data suggest that FADD may have a vital role in the development of drug resistance in pancreatic cancer cells.

The function of FADD tumors treatment

The FADD gene is located on chromatosome 11q13.3 in humans, which consists of two exons separated by a 2-kb intron and only one isoform. FADD is found in every adult and embryonic tissue in humans and mice. FADD expression is changed in many cancer types. However, this is a controversial issue since both overexpression and downregulation have been detected, depending on the cancer type. On the basis of The Human Protein Atlas, FADD protein expressions are less in many normal tissues. In cancer, FADD is examined in all tumor cells analyzed via RNA sequencing according of The Cancer Genome Atlas (TCGA), and expressions of FADD tested by immunohistochemistry reveal results that are in accord with gene and/or protein/RNA-seq characterization data. In tumor types with frequent FADD amplification, such as neck and head cancer, it has been indicated that combined treatment with radiation and SMAC mimetics may be overtly useful as FADD is key in sensitization to cell death. Also, some chemotherapeutic agents—such as Nortriptyline in bladder cancer cells or Carboplatin in tongue carcinoma—induce the expression of FADD, thus contributing to tumor cell susception to apoptosis. In chronic lymphocytic leukemia, it has been discovered that the suppression of histone deacetylase with Romidepsin plays an apoptosis sensitization effect molecularly mediated by enhanced FADD recruitment to the death-inducing signaling complex. In KRAS-driven lung cancer, it has been suggested that the suppression of FADD phosphorylation inhibites tumor development, suggesting that FADD kinase is a plausible therapeutic target. A summary of the FADD alterations reported in different cancer types is depicted in Figure 1.

Figure 1. Alterations of FADD levels reported in different cancer types.

References:

Zhuang, H., Wang, X., Zha, D., Gan, Z., Cai, F., Du, P., Yang, Y., Yang, B., Zhang, X., Yao, C., Zhou, Y., Jiang, C., Guan, S., Zhang, X., Zhang, J., Jiang, W., Hu, Q., & Hua, Z. C. (2016). FADD is a key regulator of lipid metabolism. EMBO molecular medicine, 8(8), 895–918.
Marín-Rubio, J. L., Vela-Martín, L., Fernández-Piqueras, J., & Villa-Morales, M. (2019). FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications. Cancers, 11(10), 1462.
Zhang, R., Liu, Y., Hammache, K., He, L., Zhu, B., Cheng, W., & Hua, Z. C. (2017). The role of FADD in pancreatic cancer cell proliferation and drug resistance. Oncology letters, 13(3), 1899–1904.

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