Kap1 regulates the self-renewal of embryonic stem cells and cellular reprogramming by modulating Oct4 protein stability

Kyoung, Eun; Moon, Hye Ji; Kang, Kyung Taek; Yoon, Jaesik; Kim, Ye Seul; Seo, Jeong Kon; Kim, Jae Ho

doi:10.1038/s41418-020-00613-x

Cited by 13 publications

(7 citation statements)

References 40 publications

(49 reference statements)

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“…Recently Do et al determined that Trim28 prevents the degradation of Oct4, and Trim28 overexpression stabilizes Oct4 in mouse ESC [81]. Furthermore, they found the Trim28 CC domain to be responsible for interaction with Oct4.…”

Section: Discussionmentioning

confidence: 99%

Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs

Mazurek

Oleksiewicz

Czerwińska

et al. 2021

Cells

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TRIM28, a multi-domain protein, is crucial in the development of mouse embryos and the maintenance of embryonic stem cells’ (ESC) self-renewal potential. As the epigenetic factor modulating chromatin structure, TRIM28 regulates the expression of numerous genes and is associated with progression and poor prognosis in many types of cancer. Because of many similarities between highly dedifferentiated cancer cells and normal pluripotent stem cells, we applied human induced pluripotent stem cells (hiPSC) as a model for stemness studies. For the first time in hiPSC, we analyzed the function of individual TRIM28 domains. Here we demonstrate the essential role of a really interesting new gene (RING) domain and plant homeodomain (PHD) in regulating pluripotency maintenance and self-renewal capacity of hiPSC. Our data indicate that mutation within the RING or PHD domain leads to the loss of stem cell phenotypes and downregulation of the FGF signaling. Moreover, impairment of RING or PHD domain results in decreased proliferation and impedes embryoid body formation. In opposition to previous data indicating the impact of phosphorylation on TRIM28 function, our data suggest that TRIM28 phosphorylation does not significantly affect the pluripotency and self-renewal maintenance of hiPSC. Of note, iPSC with disrupted RING and PHD functions display downregulation of genes associated with tumor metastasis, which are considered important targets in cancer treatment. Our data suggest the potential use of RING and PHD domains of TRIM28 as targets in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs

Mazurek

Oleksiewicz

Czerwińska

et al. 2021

Cells

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“…Additionally, previous studies suggested that HPV16 E6 upregulated OCT4 expression by targeting HDAC1 for proteasomal degradation ( 17 , 28 b). Moreover, JNK-phosphorylated OCT4 reduced OCT4 protein stability which was enhanced by KAP1 overexpression ( 29 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1

Shu

Liu

et al. 2022

Front. Oncol.

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Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

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“…In conventional approaches, immunoblotting was used to test the level of putative substrate ubiquitination through anti-Ub antibodies [29]. If the immunoblotting result suggested ubiquitination on the substrates, the putative ubiquitinated lysine was further mutated and analyzed by immunoblotting to evaluate whether the mutated lysine was ubiquitinated or not [30,31]. Using this kind of strategy, Ortiz et al found that the ubiquitination level of Merkel cell polyomavirus large tumor (LT) antigen was significantly reduced when K585 was substituted with R585, indicating that K585 is the ubiquitination site [32].…”

Section: Insights Into Ubiquitination At the Protein Levelmentioning

confidence: 99%

Current methodologies in protein ubiquitination characterization: from ubiquitinated protein to ubiquitin chain architecture

Sun

Zhang

2022

Cell Biosci

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Ubiquitination is a versatile post-translational modification (PTM), which regulates diverse fundamental features of protein substrates, including stability, activity, and localization. Unsurprisingly, dysregulation of the complex interaction between ubiquitination and deubiquitination leads to many pathologies, such as cancer and neurodegenerative diseases. The versatility of ubiquitination is a result of the complexity of ubiquitin (Ub) conjugates, ranging from a single Ub monomer to Ub polymers with different length and linkage types. To further understand the molecular mechanism of ubiquitination signaling, innovative strategies are needed to characterize the ubiquitination sites, the linkage type, and the length of Ub chain. With advances in chemical biology tools, computational methodologies, and mass spectrometry, protein ubiquitination sites and their Ub chain architecture have been extensively revealed. The obtained information on protein ubiquitination helps to crack the molecular mechanism of ubiquitination in numerous pathologies. In this review, we summarize the recent advances in protein ubiquitination analysis to gain updated knowledge in this field. In addition, the current and future challenges and barriers are also reviewed and discussed.

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Kap1 regulates the self-renewal of embryonic stem cells and cellular reprogramming by modulating Oct4 protein stability

Cited by 13 publications

References 40 publications

Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs

Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1

Current methodologies in protein ubiquitination characterization: from ubiquitinated protein to ubiquitin chain architecture

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