Targeting protein–protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs)

Sammak, Susan; Zinzalla, Giovanna

doi:10.1016/j.pbiomolbio.2015.06.004

Cited by 31 publications

(32 citation statements)

References 73 publications

(26 reference statements)

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“…Studies on animal mouse models have shown that c-Myc inhibition can completely stop tumour growth and can also inhibit cancer stem cell progression. 31 However, it is very difficult to target IDPs. It was suggested that there are 2 possible binding modes of inhibition to c-Myc:Max.…”

Section: Therapeutic Target and Drug Developmentmentioning

confidence: 99%

“…59 A mass spectrometry–based method was developed to characterize different binding modes of synthetic inhibitors, and it was observed that most of the promising inhibitors were following first mode of binding to the c-Myc, which was named trap mode. 31 Peptidomimetic screening of compound libraries has yielded 2 molecules, IIA6B17 and IIA4B20, which were found to disrupt initial formation of Myc:MAX dimers. Subsequently, other molecules, mycmycin-1 and mycmycin-2, were derived from previous molecules to improve the specificity of the inhibition.…”

Section: Therapeutic Target and Drug Developmentmentioning

confidence: 99%

“…Transcription factors are one of the types of proteins in eukaryotic proteome that act as central hub to regulate gene expression. 31 In further part of the review, we shed light on IDP perspective of TFs and role of c-Myc as disordered protein TF.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

2017

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The concept of protein intrinsic disorder has taken the driving seat to understand regulatory proteins in general. Reports suggest that in mammals nearly 75% of signalling proteins contain long disordered regions with greater than 30 amino acid residues. Therefore, intrinsically disordered proteins (IDPs) have been implicated in several human diseases and should be considered as potential novel drug targets. Moreover, intrinsic disorder provides a huge multifunctional capability to hub proteins such as c-Myc and p53. c-Myc is the hot spot for understanding and developing therapeutics against cancers and cancer stem cells. Our past understanding is mainly based on in vitro and in vivo experiments conducted using c-Myc as whole protein. Using the reductionist approach, c-Myc oncoprotein has been divided into structured and disordered domains. A wealth of data is available dealing with the structured perspectives of c-Myc, but understanding c-Myc in terms of disordered domains has just begun. Disorderness provides enormous flexibility to proteins in general for binding to numerous partners. Here, we have reviewed the current progress on understanding c-Myc using the emerging concept of IDPs.

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Section: Therapeutic Target and Drug Developmentmentioning

confidence: 99%

Section: Therapeutic Target and Drug Developmentmentioning

confidence: 99%

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Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

2017

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“…Within the network, one transcription factor target more than three LASP-1 interactor genes, and one LASP-1 interactor was mainly controlled by at least three transcription factors. Because current studies show that the function of transcription factors is based on the interaction with other proteins48, we investigated whether the expression of LASP-1 and its interactors associated with HBV-related HCC was potentially regulated by the interaction of different transcription factors. Using the STRING platform, we found that 13 transcription factors interact with others (Supplementary Table S11) and form a complex interaction network (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The results suggested that the expression of target genes was mainly controlled by 22 predicted transcription factors. Current studies suggest that cooperativity between transcription factors is vital in the regulation of gene expression48. In addition, with the development of high-throughput technology and computer prediction methods, several interactions with transcription factors were identified646566.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of the proteins interacting with LASP-1 and their association with HBV-related hepatocellular carcinoma

Kong

Zhu

et al. 2017

Sci Rep

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LIM and SH3 domain protein (LASP-1) is responsible for the development of several types of human cancers via the interaction with other proteins; however, the precise biological functions of proteins interacting with LASP-1 are not fully clarified. Although the role of LASP-1 in hepatocarcinogenesis has been reported, the implication of LASP-1 interactors in HBV-related hepatocellular carcinoma (HCC) is not clearly evaluated. We obtained information regarding LASP-1 interactors from public databases and published studies. Via bioinformatics analysis, we found that LASP-1 interactors were related to distinct molecular functions and associated with various biological processes. Through an integrated network analysis of the interaction and pathways of LASP-1 interactors, cross-talk between different proteins and associated pathways was found. In addition, LASP-1 and several its interactors are significantly altered in HBV-related HCC through microarray analysis and could form a complex co-expression network. In the disease, LASP-1 and its interactors were further predicted to be regulated by a complex interaction network composed of different transcription factors. Besides, numerous LASP-1 interactors were associated with various clinical factors and related to the survival and recurrence of HBV-related HCC. Taken together, these results could help enrich our understanding of LASP-1 interactors and their relationships with HBV-related HCC.

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Development of Cell‐Permeable, Non‐Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer

Wiedmann

Tan

et al. 2016

Angewandte Chemie

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There is al acko fc urrent treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics.T he transcription factor hepatocyte nuclear factor 1b (HNF1b)isubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1b,i nf ive high-and low-HNF1b-expressing CCC lines.T oi nhibit the protein function, cellpermeable,n on-helical constrained proteomimetics to target the HNF1b-importin a protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations.I nt his way, we developed the first reported series of constrained peptide nuclear import inhibitors.I mportantly,t his general approach may be extended to other transcription factors.The prognosis for ovarian clear cell carcinoma (CCC) patients with advanced-stage disease is poor owing to intrinsic resistance to platinum-based chemotherapy and the lack of targeted therapies available.[1] Overexpression of the hepatocyte nuclear factor 1b (HNF1b)t ranscription factor is the most important clinical immunohistochemical marker for the disease,s ince it is ubiquitously overexpressed in CCC. [2] However,t od ate,d rugs targeting HNF1b have not been developed due to the high content of intrinsically disordered regions in transcription factors. [3] Evidence that targeting HNF1b is av iable and attractive approach for developing anew targeted therapy was initially provided by Liu et al.,w ho showed that downregulation of HNF1b increased cisplatin-and paclitaxel-mediated cytotoxicity.[4] HNF1b is expressed in the liver,d igestive tract, pancreas,a nd kidneys,w here it plays ar ole in early differentiation.[5] Human HNF1b is made up of three domains:the dimerization domain;t he transactivation domain, which is involved in binding transcriptional coactivators;a nd the DNA-binding domain (DBD). We have recently confirmed the existence of anuclear localization signal (NLS) within the DBD of HNF1b, [6] which directs the nuclear import of the protein. [7] Many NLS sequences are recognized in the cytoplasm by ah eterodimeric transport carrier complex composed of importin a and importin b.[8] Classical NLSs (cNLS) can bind to importin a through either am ajor site,aminor site, or both. [8,9] Monopartite cNLSs consist of as ingle cluster of positively charged residues,primarily lysines or arginines,that assume an ordered state once bound to importin a. [10] Therapeutic targeting of the nuclear import of transcription factors provides as trategy for inhibiting their function, since activity depends on successful localization to the nucleus for transcription to take place.[11] Lin et al. developed a4 1-residue synthetic peptide called cSN50 that contains the NF-kBN LS and ac ell-permeable motif.[12] The peptide inhibits the nuclear translocation of NF-kB, attenu- Supportinginformation (including all data supporting t...

show abstract

Targeting protein–protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs)

Cited by 31 publications

References 73 publications

Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

Bioinformatics analysis of the proteins interacting with LASP-1 and their association with HBV-related hepatocellular carcinoma

Development of Cell‐Permeable, Non‐Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer

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