UNC5 dependence receptor family in human cancer: A controllable double-edged sword

Zhu, Yuyan; Li, Yuanyuan; Nakagawara, Akira

doi:10.1016/j.canlet.2021.05.034

Cited by 10 publications

(9 citation statements)

References 61 publications

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“…Their intracellular domain is composed of a ZU-5 — UPA — DD (ZUD) module, similar to the one found on the PIDD1 C-terminus. UNC5 receptors are widely expressed during neural development where they are involved in axonal guidance and cell migration [ 42 ] and function as dependence receptors with additional roles in apoptosis and tumorigenesis [ 43 ]. Interestingly, Wang et al [ 29 ] established that within this ZUD module, the UPA and DD fold back onto the ZU-5 domain, thereby sequestering the DD in an inhibitory state and preventing the induction of apoptosis.…”

Section: The P53-induced Death Domain Protein 1 (Pidd1)mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

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The death fold domain-containing protein PIDD1 has recently attracted renewed attention as a regulator of the orphan cell death-related protease, Caspase-2. Caspase-2 can activate p53 to promote cell cycle arrest in response to centrosome aberrations, and its activation requires formation of the PIDDosome multi-protein complex containing multimers of PIDD1 and the adapter RAIDD/CRADD at its core. However, PIDD1 appears to be able to engage with multiple client proteins to promote an even broader range of biological responses, such as NF-κB activation, translesion DNA synthesis or cell death. PIDD1 shows features of inteins, a class of self-cleaving proteins, to create different polypeptides from a common precursor protein that allow it to serve these diverse functions. This review summarizes structural information and molecular features as well as recent experimental advances that highlight the potential pathophysiological roles of this unique death fold protein to highlight its drug-target potential.

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Section: The P53-induced Death Domain Protein 1 (Pidd1)mentioning

confidence: 99%

PIDD1 in cell cycle control, sterile inflammation and cell death

Weiler

Szabó

Villunger

2022

Biochemical Society Transactions

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“…Interestingly, caspases responsible for DR cleavages involve both “initiator” (caspases 2, 8, 9, 10, and 12) and “effector” caspases (caspases 3, 6, and 7). For instance, upon withdrawal of their respective ligand, the intracellular regions of UNC5B or c‐KIT are cleaved by caspase‐3, UNC5D can be cleaved by caspase‐2 or 3, while EphB3 can be cleaved by caspase‐8 or 9 (Abbaspour Babaei et al , 2016; Tsenkina et al , 2020; Zhu et al , 2021). Moreover, studies reveal that DCC can interact with caspase‐3 or caspase‐9 depending on its conformation, suggesting implication of one of these caspases in DCC cleavage (Forcet et al , 2001).…”

Section: The Dependence Receptor Paradigmmentioning

confidence: 99%

“…DR cleavage by caspases leads to their conformational modification, most frequently resulting in the exposure of a dependence domain of these receptors that remains anchored to the extracellular membrane. In contrast, the dependence domain of a few DRs (c‐MET, RET, TrkC, c‐Kit, and UNC5H receptors) is released in the cytoplasm (Bordeaux et al , 2000; Tulasne et al , 2004; Wang et al , 2018; Zhu et al , 2021). Exposure or release of dependence domains leads to the recruitment and activation of apoptotic partners, most frequently caspases.…”

Section: The Dependence Receptor Paradigmmentioning

confidence: 99%

Dependence receptors: new targets for cancer therapy

et al. 2021

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Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro‐apoptotic functions of these proteins.

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“…UNC-5 family members, including four homologs (UNC5A-D), were identified as receptors of netrin-1 [ 7 ]. Due to their ability to trigger apoptosis in the absence of netrin-1, UNC5 receptors have been reported to function as dependence receptors [ 8 ]. For instance, apoptosis induced by UNC5 receptors in normal colonic epithelium is precisely regulated by varied expression of netrin-1, with highest expression in the crypts and lowest expression in the upper portion of the villi [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…This indicated that the system may play essential roles in maintaining the normal intestinal epithelial microenvironment, and its de-regulation might promote the formation of hyperplasia, adenoma, or adenocarcinoma [ 10 ]. Therefore, UNC5 receptors have been proposed as putative tumr suppressor genes, with down-regulated expression in a variety of human malignancies due to genetic and epigenetic alterations [ 8 ]. We previously showed that loss of heterozygosis and DNA methylation contributed to the inactivation of UNC5C [ 11 ] and UNC5D [ 12 ] in renal cell carcinoma.…”

Section: Introductionmentioning

confidence: 99%

Promoter methylation-mediated repression of UNC5 receptors and the associated clinical significance in human colorectal cancer

et al. 2021

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Background Deregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis. UNC5 receptors, down-regulated in various human malignancies due to epigenetic alterations, have been proposed as putative tumor suppressor genes. In this study, we focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC. Methods Methylation and expression analysis was performed in TCGA datasets. And the results were confirmed in vitro in CRC cell lines treated with 5-aza-deoxycytidine. Then, the expression and epigenetic alterations of UNC5 receptors were evaluated in clinical specimens. Moreover, the diagnostic and prognostic values of the methylation alterations were also analyzed. Results Methylation-mediated repression was observed in UNC5C and UNC5D, but not in UNC5A and UNC5B, which was confirmed in CRC cell lines. Except for UNC5B, significantly elevated methylation was observed in UNC5A, UNC5C, and UNC5D in CRC. The discrimination efficiency of the three receptors was comparable with that of SEPT9. Kaplan–Meier curve survival analysis showed that hypermethylation of UNC5A, UNC5C and UNC5D was associated with poor progression-free and overall survival. Moreover, methylation levels of UNC5C and UNC5D were independent predictors of CRC progression-free (P = 0.001, P = 0.003, respectively) and overall survival (P = 0.008, P = 0.004, respectively). Conclusions Hypermethylation of UNC5C and UNC5D mediates the repression and has promising diagnostic and prognostic values in CRC.

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UNC5 dependence receptor family in human cancer: A controllable double-edged sword

Cited by 10 publications

References 61 publications

PIDD1 in cell cycle control, sterile inflammation and cell death

PIDD1 in cell cycle control, sterile inflammation and cell death

Dependence receptors: new targets for cancer therapy

Promoter methylation-mediated repression of UNC5 receptors and the associated clinical significance in human colorectal cancer

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