BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation

Shabbeer, Shabana; Omer, Dorit; Berneman, Dana; Weitzman, Osnat; Alpaugh, Alexandra; Pietraszkiewicz, Alexandra; Metsuyanim, Sally; Shainskaya, Alla; Papa, Moshe Z.; Yarden, Ronit I.

doi:10.1038/onc.2012.522

Cited by 56 publications

(63 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They are involved in mitomycin-C (MMC)-induced DNA repair, the association of Fanconi anemia complex with the E3 ubiquitin-protein ligase FANCL, and catalyzing the monoubiquitination of FANCD2 [3, 4]. They also contribute to the ubiquitination and degradation of BRCA1 [5, 6]. Ubiquitin-conjugating enzyme E2T (UBE2T) combines with a specific E3 ubiquitin ligase to induce the degradation of or functional changes in substrate molecules.…”

Section: Introductionmentioning

confidence: 99%

UBE2T knockdown inhibits gastric cancer progression

Luo

Yao

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Ubiquitin-conjugating enzymes (E2 enzymes) such as UBE2T target proteins for degradation via the proteasome. Here, we examined the effects of UBE2T on the progression of gastric cancer. UBE2T was highly expressed in gastric tumors and gastric cancer cells. siRNA-mediated suppression of UBE2T inhibited gastric cancer cell proliferation and colony formation by promoting cell cycle arrest at G2/M phase and increasing apoptosis. Suppression of UBE2T also attenuated the invasive and metastatic abilities of gastric cancer cells by altering expression of epithelial-mesenchymal transition (EMT)-related factors. A xenograft model in which nude mice were injected with UBE2T knockdown human gastric cancer cells confirmed that suppression of UBE2T also decreased tumor formation and growth in vivo. Expression levels of CCND1, Phospho-GSK3B, WNT family members, and MYC were all affected by UBE2T knockdown. These results suggest that UBE2T plays a critical role in gastric cancer, and that it may serve as a useful prognostic biomarker and therapeutic target in gastric cancer patients.

show abstract

Section: Introductionmentioning

confidence: 99%

UBE2T knockdown inhibits gastric cancer progression

Luo

Yao

et al. 2017

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Here, the BRCA1/BARD1 complex was identified as an E3 ligase for Cdc25C. 58,59 In all of these studies, the decrease in Cdc25C protein levels was mediated by the proteasome, and some of these reports provided evidence of ubiquitination of Cdc25C. 40,56,58 …”

Section: Discussionmentioning

confidence: 96%

Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase

et al. 2017

View full text Add to dashboard Cite

Upon different types of stress, the gene encoding the mitosis-promoting phosphatase Cdc25C is transcriptionally repressed by p53, contributing to p53’s enforcement of a G2 cell cycle arrest. In addition, Cdc25C protein stability is also decreased following DNA damage. Mdm2, another p53 target gene, encodes a ubiquitin ligase that negatively regulates p53 levels by ubiquitination. Ablation of Mdm2 by siRNA led to an increase in p53 protein and repression of Cdc25C gene expression. However, Cdc25C protein levels were actually increased following Mdm2 depletion. Mdm2 is shown to negatively regulate Cdc25C protein levels by reducing its half-life independently of the presence of p53. Further, Mdm2 physically interacts with Cdc25C and promotes its degradation through the proteasome in a ubiquitin-independent manner. Either Mdm2 overexpression or Cdc25C downregulation delays cell cycle progression through the G2/M phase. Thus, the repression of the Cdc25C promoter by p53, together with p53-dependent induction of Mdm2 and subsequent degradation of Cdc25C, could provide a dual mechanism by which p53 can enforce and maintain a G2/M cell cycle arrest.

show abstract

“…Both BRCA1 and BRCA2 suppress the cell cycle progression [6-8]. Cancer cells in tissues of BRCA1 or BRCA2 mutation carriers are usually near tetraploid/polyploidy [9,10].…”

Section: Introductionmentioning

confidence: 99%

The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy

Wang

Zhou

et al. 2014

Mol Cancer

View full text Add to dashboard Cite

It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.

show abstract

BRCA1 targets G2/M cell cycle proteins for ubiquitination and proteasomal degradation

Cited by 56 publications

References 52 publications

UBE2T knockdown inhibits gastric cancer progression

UBE2T knockdown inhibits gastric cancer progression

Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase

The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy

Contact Info

Product

Resources

About