Ubiquitin E3 Ligase CRL4CDT2/DCAF2 as a Potential Chemotherapeutic Target for Ovarian Surface Epithelial Cancer

Pan, Weiwei; Zhou, Jian-Jie; Yu, Chao; Xu, Ying; Guo, Lian-Jun; Zhang, Haiyi; Zhou, Dawang; Song, Fangzhou; Fan, Heng‐Yu

doi:10.1074/jbc.m113.495069

Cited by 70 publications

(79 citation statements)

References 37 publications

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“…2F), suggesting that IP6K1 prevents c-Jun ubiquitylation and degradation. In line with this notion, MLN-4924, a NEDD8-activating enzyme inhibitor that reduces the neddylation and catalytic activity of CRL4 (31,32), dose-dependently increases levels of c-Jun in IP6K1-null, but not wild-type, MEFs (Fig. 2G).…”

Section: Ip6k1supporting

confidence: 66%

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death

Rao

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Inositol polyphosphates containing an energetic pyrophosphate bond are formed primarily by a family of three inositol hexakisphosphate (IP6) kinases (IP6K1-3). The Cullin-RING ubiquitin ligases (CRLs) regulate diverse biological processes through substrate ubiquitylation. CRL4, comprising the scaffold Cullin 4A/B, the E2-interacting Roc1/2, and the adaptor protein damage-specific DNA-binding protein 1, is activated by DNA damage. Basal CRL4 activity is inhibited by binding to the COP9 signalosome (CSN). UV radiation and other stressors dissociate the complex, leading to E3 ligase activation, but signaling events that trigger signalosome dissociation from CRL4 have been unclear. In the present study, we show that, under basal conditions, IP6K1 forms a ternary complex with CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. Thus, IP6K1 is a novel CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death. Inositol pyrophosphates containing seven (IP7) or more phosphate groups on a myo-inositol ring are synthesized from inositol hexakisphosphate (IP6) primarily by a family of IP6 kinases that are conserved from yeast to humans and mediate diverse physiologic functions (1, 2). Among the three mammalian IP6K isoforms, IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (3). IP6K1 plays a role in diabetes (4), DNA homologous recombination (HR) repair (5), spermatogenesis (6), and chromatin modifications (7).The Cullin-RING ubiquitin ligases (CRLs) control fundamental biological processes by mediating 20% of ubiquitindependent protein turnover (8). These E3 ligases are multiprotein complexes composed of the scaffold Cullins (Cul 1-7), the E2-interacting RING-finger protein Roc1/2, adaptor proteins specific for each Cullin family member, and adaptor-interacting substrate receptors that target substrates for ubiquitylation. CRL4, a DNA-damage-sensing member of this family (9), mediates the degradation of numerous substrates involved in cell cycle regulation (CDT1, p21, p27) as well as cell growth or death (c-Jun, p53) and is aberrantly active in many tumor types (10). The CRL4 complex comprises Cul4A/B and the adaptor protein damagespecific DNA binding protein 1 (DDB1). DDB1 binds to a family of WD40 domain-containing proteins that are substrate receptors (11, 12). The complex of DDB1 and its substrate receptor DDB2 binds directly to UV-damaged DNA to initiate nucleotide excision repair (NER) by ubiquitylating local histones and the NER machinery (9). Loss of DDB activity results in group E xeroderma pigmentosum, whose victims are hypersensitive to UV light. However, it remains unclear how CRL4 is activated by UV.In plants, CRL4 is also regulated by UV. Thus, UV absorption by tryptophan residues in the dimer interface of UV-B Resistance 8 (UVR8) triggers dimer dissociation (13). Monomeric UVR8 binds and seque...

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Section: Ip6k1supporting

confidence: 66%

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death

Rao

Khan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, small molecules that modulate the PI3K pathway have been used for treating the ovarian tissues of human primary ovarian insufficiency patients for assisted reproduction purposes . In comparison, inhibitors of the CRL family ubiquitin E3 ligases have been used for cancer therapy (Pan et al, 2013). Our observations in these novel mouse models suggest that the key role of CRL4 DCAF1 in oocytes of growing follicles should be considered when using these new drugs in medical practice.…”

Section: Implications For Human Primary Ovarian Insufficiencymentioning

confidence: 88%

CRL4DCAF1 is required in activated oocytes for follicle maintenance and ovulation

Sha

et al. 2014

Molecular Human Reproduction

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In mammals, oocytes within the primordial follicles require a number of essential factors to maintain their survival. However, the survival factors for activated oocytes have been poorly characterized. Recently we reported that damaged DNA binding protein-1 (DDB1), the linker subunit of the cullin ring-finger ubiquitin E3 ligase-4 (CRL4) complex, and its substrate adaptor, DDB1-CUL4 associated factor-1 (DCAF1), were essential for primordial follicle maintenance. In this study we specifically deleted these in the oocytes of growing follicles, to investigate if DDB1 and DCAF1 were also survival factors for activated oocytes. In the ovaries of Ddb1 fl/fl ;Zp3-Cre mice, the primordial follicle pool was intact, but awakened oocytes and growing follicles beyond the primary stage were rapidly depleted. In the ovaries of Dcaf1 fl/fl ;Pten fl/fl ;Gdf9-Cre and Ddb1 fl/fl ;Pten fl/fl ;Gdf9-Cre mice, global primordial follicle activation was stimulated by enhanced PI3K signaling, but the awakened oocytes were rapidly lost due to no CRL4 DCAF1 activity. These mouse models provided original evidence that CRL4 DCAF1 was essential for maintaining oocyte survival, not only those in dormancy at the primordial follicle stage, but also naturally awakened oocytes and those awakened by hyperactivation of PI3K signaling. Interestingly, the oocyte-specific Ddb1 or Dcaf1 knockout mice had ovulation defects even before oocyte exhaustion. CRL4 DCAF1 within oocytes was required for cumulus expansion and ovulation-related somatic gene expression in a cell non-autonomous manner.Granulosa cells that surrounded these Ddb1 or Dcaf1-deleted oocytes exhibited increased rates of apoptosis and showed poor responses to ovulation signals. These results suggested that CRL4 in oocytes also regulated granulosa cell functions in a cell non-autonomous manner.

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“…However, the toxicity and the development of resistance often limit its efficacy (33). Previously, a series of studies revealed that MLN4924 could be used as a sensitizer to chemotherapy: MLN4924 has been demonstrated to overcome resistance to a range of chemotherapeutics, including CDDP (20,21), carboplatin (21,34), bleomycin (35), doxorubicin (35) and etoposide (35) resistance in ovarian tumor cell lines in vitro and in vivo. MLN4924 significantly augmented the cytotoxicity of CDDP against CDDP-resistant cells in cervical carcinoma xenografts (22).…”

Section: Discussionmentioning

confidence: 99%

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

Lin

Shang

et al. 2017

Oncol Lett

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Abstract. Inhibiting the protein neddylation pathway using the NEDD8-activating enzyme inhibitor MLN4924 represents an attractive anticancer strategy having been demonstrated to exhibit promising anticancer efficacy and with tolerable levels of toxicity; however, the mechanism by which MLN4924 inhibits cell proliferation in human esophageal squamous cell carcinoma (ESCC) cells requires further investigation. The present study revealed that MLN4924 treatment led to G 2 cell cycle arrest and enhanced the protein stability of Wee1-like protein kinase and cyclin dependent protein kinase inhibitor 1A and B and p27. Furthermore, MLN4924 induced DNA damage and sensitized esophageal cancer cells to cisplatin by enhancing apoptosis. These findings extend the understanding of the function and mechanism of MLN4924 in ESCC and provide further evidence for the future development of neddylation inhibitors in clinical trials of esophageal cancer therapy, either alone or in combination.

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Ubiquitin E3 Ligase CRL4CDT2/DCAF2 as a Potential Chemotherapeutic Target for Ovarian Surface Epithelial Cancer

Cited by 70 publications

References 37 publications

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death

Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4–signalosome complex to regulate DNA repair and cell death

CRL4DCAF1 is required in activated oocytes for follicle maintenance and ovulation

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

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