The interactome of CCT complex – A computational analysis

Narayanan, Aswathy; Pullepu, Dileep; Kabir, M. Anaul

doi:10.1016/j.compbiolchem.2016.09.002

Cited by 24 publications

(28 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of siRNAs to target different CCT subunits was previously explored by others in select cell lines and resulted in growth arrest that was independent of checkpoint inhibition and reductions in tubulin but not actin 42 . Further evidence supporting the important role of CCT in cell cycling come from studies showing that key cell cycle mediators like Cdc20 44 , CDK2/cyclin E 45 , Polo-like kinase 1 (PLK1) 46 and others are folded and assembled by CCT 30,33 , which in part explains why CCT levels increase during S phase 47 . Moreover, the CCT chaperonin was recently found to have role in the disassembly of mitotic checkpoint complexes 48 as well as mediating calcium signaling through Orai1 trafficking 49 .…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports estimated that in eukaryotic cells, CCT facilitates the folding of approximately 10% of newly synthesized proteins, co-and post-translationally [27][28][29] , with actin and tubulin being obligate substrates 30 . In cancer cells, CCT could potentially fold more proteins, with substrates including oncogenic proteins and mediators such as KRAS, STAT3, among others 14,20,[31][32][33] . Genomic amplification of CCT or upregulation of gene expression suggests that CCT could be a marker for oncogenesis 34 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Showalter

Martini

Nierenberg

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Chaperonin-containing TCP-1 (CCT or TRiC) is a multi-subunit complex that folds many of the proteins essential for cancer development. CCT is expressed in diverse cancers and could be an ideal therapeutic target if not for the fact that the complex is encoded by eight distinct genes, complicating the development of inhibitors. Few definitive studies addressed the role of specific subunits in promoting the chaperonin's function in cancer. To this end, we investigated the activity of CCT2 (CCTβ) by overexpressing or depleting the subunit in breast epithelial and breast cancer cells. We found that increasing total CCT2 in cells by 1.3-1.8-fold using a lentiviral system, also caused CCT3, CCT4, and CCT5 levels to increase. Likewise, silencing cct2 gene expression by ~50% caused other CCT subunits to decrease. Cells expressing CCT2 were more invasive and had a higher proliferative index. CCT2 depletion in a syngeneic murine model of triple negative breast cancer (TNBC) prevented tumor growth. These results indicate that the CCT2 subunit is integral to the activity of the chaperonin and is needed for tumorigenesis. Hence CCT2 could be a viable target for therapeutic development in breast and other cancers. The hallmarks of cancer (uncontrolled proliferation, genomic instability, metastasis, etc.) reveal the complex nature of this disease and the challenges faced developing effective therapeutics 1,2. Cancer does, however, have an "Achilles heel" and that is its dependency or addiction on major cellular events or processes like transcription, translation, splicing, protein degradation and protein-folding 3. In healthy cells, such conserved and essential processes are rigorously regulated by the proteostasis network (PN) to ensure proteome balance. In order to maintain proteome integrity, the cellular proteome must be synthesized, folded into its native structure, and, when no longer needed, degraded and the amino acids recycled 4,5. Chaperones and chaperonins are key players in the PN 6. Unlike healthy, non-transformed cells, the PN of cancer cells is taxed to produce proteins involved in survival, angiogenesis, migration, proliferation which are essential for tumor formation, progression and metastasis. Cancer cells have a higher dependency on molecular chaperones and are uniquely challenged due to imbalances caused by chromosomal abnormalities and overexpression of oncogenes, ultimately leading to cellular stress 7. As example, inhibitors of Heat Shock Protein 90 (HSP90) showed promising outcomes in the treatment of metastatic breast cancer 8. However, despite being in clinical trials since 1998, the success of HSP90 inhibitors in clinical trials remains mixed 9-11. Reasons such as dose-limiting toxicity, incomplete inhibition of HSP90, and insufficient downregulation of client proteins impeded the clinical use of current HSP90 inhibitors 12,13. In recent years,

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

Showalter

Martini

Nierenberg

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Seven of the nine members of the HSP60 protein family of chaperonins (Fig. 3D) are found in our list due to their role in c-Myc protein folding (Narayanan et al 2016;Carr et al 2017). Finally, PDIA6 and VCP can modulate c-Myc protein levels in bladder and osteosarcoma cancer cells, respectively (Cheng et al 2017;Heidelberger et al 2018).…”

Section: New C-myc Rbps Identified By Hypr-msmentioning

confidence: 91%

“…In line with this, both IVs and EVs are enriched GO terms by gene ontology analysis (Supplemental Table S3). For proteins not explained in the text we refer to related citations delineating their roles in mRNA processing: a (Harshman et al 2013 (Caplan 2003;Chen et al 2005;Zheng et al 2011;Saibil 2013;Halperin et al 2014;Briones 2015;Gao et al 2016;Narayanan et al 2016). See Supplemental Table S3 for c-Myc RBPs belonging to these specific subgroups.…”

Section: Characterization Of the C-myc Protein Interactomementioning

confidence: 99%

Comprehensive in vivo identification of the c-Myc mRNA protein interactome using HyPR-MS

Spiniello

Steinbrink

Cesnik

et al. 2019

RNA

View full text Add to dashboard Cite

Proteins bind mRNA through their entire life cycle from transcription to degradation. We analyzed c-Myc mRNA protein interactors in vivo using the HyPR-MS method to capture the crosslinked mRNA by hybridization and then analyzed the bound proteins using mass spectrometry proteomics. Using HyPR-MS, 229 c-Myc mRNA-binding proteins were identified, confirming previously proposed interactors, suggesting new interactors, and providing information related to the roles and pathways known to involve c-Myc. We performed structural and functional analysis of these proteins and validated our findings with a combination of RIP-qPCR experiments, in vitro results released in past studies, publicly available RIP-and eCLIP-seq data, and results from software tools for predicting RNA-protein interactions.

show abstract

“…For instance, many of them have complex topologies that are stabilized in the native structure by long-range contacts. As a result, many chaperonin substrates have rugged folding landscapes in which kinetically trapped folding intermediates and misfolded states are frequently populated (14,(63)(64)(65). However, whether or not client encapsulation generally affects the folding landscape of chaperone clients, and in doing so enhances folding rates, is not yet clear.…”

Section: Hsp60mentioning

confidence: 99%