KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies

Briers, Stephanie; Crawford, Catherine; Bickmore, Wendy A.; Sutherland, Heidi G.

doi:10.1242/jcs.034793

Cited by 18 publications

(15 citation statements)

References 48 publications

(66 reference statements)

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“…Perhaps as few as four antibodies capable of detecting endogenous levels of individual KRAB-ZNF proteins have been reported (6, 34, 35). After testing multiple commercial antibodies to many KRAB-ZNFs, we were able to detect endogenous levels of ZNF192 and ZNF274.…”

Section: Resultsmentioning

confidence: 99%

KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells

et al. 2015

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KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization and the DNA damage response, acting as an essential co-repressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers. KAP1 silencing in breast cancer cells reduced proliferation and inhibited the growth and metastasis of tumor xenografts. Conversely, KAP1 overexpression stimulated cell proliferation and tumor growth. In cells where KAP1 was silenced, we identified multiple downregulated genes linked to tumor progression and metastasis, including EREG/epiregulin, PTGS2/COX2, MMP1, MMP2 and CD44, along with downregulation of multiple KRAB-ZNF proteins. KAP1-dependent stabilization of KRAB-ZNF required direct interactions with KAP1. Together, our results show that KAP1-mediated stimulation of multiple KRAB-ZNF contributes to the growth and metastasis of breast cancer.

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Section: Resultsmentioning

confidence: 99%

KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells

et al. 2015

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“…TRIM28 has been shown to function, as part of a multiprotein complex, to repress gene expression (47,65). YB-1 can interact with various transcription factors to either repress or activate gene expression (66,67).…”

Section: Discussionmentioning

confidence: 99%

A Multiprotein Binding Interface in an Intrinsically Disordered Region of the Tumor Suppressor Protein Interferon Regulatory Factor-1

Narayan¹,

Halada

Hernychová

et al. 2011

Journal of Biological Chemistry

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The interferon-regulated transcription factor and tumor suppressor protein IRF-1 is predicted to be largely disordered outside of the DNA-binding domain. One of the advantages of intrinsically disordered protein domains is thought to be their ability to take part in multiple, specific but low affinity protein interactions; however, relatively few IRF-1-interacting proteins have been described. The recent identification of a functional binding interface for the E3-ubiquitin ligase CHIP within the major disordered domain of IRF-1 led us to ask whether this region might be employed more widely by regulators of IRF-1 function. Here we describe the use of peptide aptamer-based affinity chromatography coupled with mass spectrometry to define a multiprotein binding interface on IRF-1 (Mf2 domain; amino acids 106 -140) and to identify Mf2-binding proteins from A375 cells. Based on their function as known transcriptional regulators, a selection of the Mf2 domain-binding proteins (NPM1, TRIM28, and YB-1) have been validated using in vitro and cell-based assays. Interestingly, although NPM1, TRIM28, and YB-1 all bind to the Mf2 domain, they have differing amino acid specificities, demonstrating the degree of combinatorial diversity and specificity available through linear interaction motifs.

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“…Secondary antibodies, and image capture by wide-field epifluorescence microscopy were as previously described [79]. Confocal analysis was performed using a Zeiss LSM510 confocal microscope.…”

Section: Methodsmentioning

confidence: 99%

Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing

et al. 2012

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Increasing evidence suggests that chromatin modifications have important roles in modulating constitutive or alternative splicing. Here we demonstrate that the PWWP domain of the chromatin-associated protein Psip1/Ledgf can specifically recognize tri-methylated H3K36 and that, like this histone modification, the Psip1 short (p52) isoform is enriched at active genes. We show that the p52, but not the long (p75), isoform of Psip1 co-localizes and interacts with Srsf1 and other proteins involved in mRNA processing. The level of H3K36me3 associated Srsf1 is reduced in Psip1 mutant cells and alternative splicing of specific genes is affected. Moreover, we show altered Srsf1 distribution around the alternatively spliced exons of these genes in Psip1 null cells. We propose that Psip1/p52, through its binding to both chromatin and splicing factors, might act to modulate splicing.

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KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies

Cited by 18 publications

References 48 publications

KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells

KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells

A Multiprotein Binding Interface in an Intrinsically Disordered Region of the Tumor Suppressor Protein Interferon Regulatory Factor-1

Psip1/Ledgf p52 Binds Methylated Histone H3K36 and Splicing Factors and Contributes to the Regulation of Alternative Splicing

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