FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53

Ochocka, Anna Maria; Kampanis, Petros; Nicol, Samantha M.; Allende-Vega, Nerea; Cox, Miranda; Marcar, Lynnette; Milne, Diane; Fuller-Pace, Frances V.; Meek, David W.

doi:10.1016/j.febslet.2009.01.009

Cited by 64 publications

(56 citation statements)

References 15 publications

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“…The remaining chromatin-associated interactions identified by in-solution digestion will be described in a separate publication. This link is notable in light of previous findings that FKBP25 regulates p53 levels via MDM2 (Ochocka et al 2009), and KAP1, PARP1, and RPA1 all have links to the regulation of p53 in DNA damage (Valenzuela et al 2002;Bochkareva et al 2005;Wang et al 2005). In support of a potential role for FKBP25 in chromatin biology, histone deacetylaces (HDAC) 1 and 2 have been identified as FKBP25-associated proteins (Yang et al 2001), and Mybbp1a and KAP1 are found in complexes containing HDAC1 and 2 (Schultz et al 2001;Tan et al 2012).…”

Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 66%

“…S2). In support of this, FKBP25 has an exposed nuclear localization signal (NLS), accumulates in the nucleus upon treatment with the nuclear export inhibitor Leptomycin B (LMB) (Ochocka et al 2009), and its reported functions are carried out in the nucleus. Additionally, we performed chromatin immunoprecipitation (ChIP) using antisera raised against the N terminus of FKBP25.…”

Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 93%

“…Although nucleolin was the only reported FKBP25-associated protein identified in our screen, the lack of others being identified may be explained by a cell type dependency. Although we used HEK293 cells for this study, Ochocka et al (2009) used a combination of MCF-7, U2OS, H1299 and HTC116 cells, whereas Yang et al (2001) used Jurkat and HeLa cells. Thus, in addition to a possible role in ribosome biology, FKBP25 may also regulate chromatin dynamics and the response to DNA damage.…”

Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 99%

“…Previous reports implicate FKBP25 in chromatin biology and transcription: It regulates the auto-ubiquitination and degradation of MDM2 (Ochocka et al 2009) and inhibits the DNA binding of the transcription factor YY1 (Yang et al 2001). Additionally, FKBP25 associates with two proteins that localize in the nucleolus: casein kinase II (CK2) and nucleolin (Jin and Burakoff 1993).…”

Section: Introductionmentioning

confidence: 99%

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The prolyl isomerase, FKBP25, interacts with RNA-engaged nucleolin and the pre-60S ribosomal subunit

Gudavicius

Dilworth

Serpa

et al. 2014

RNA

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Peptidyl-proline isomerases of the FK506-binding protein (FKBP) family belong to a class of enzymes that catalyze the cis-trans isomerization of prolyl-peptide bonds in proteins. A handful of FKBPs are found in the nucleus, implying that the isomerization of proline in nuclear proteins is enzymatically controlled. FKBP25 is a nuclear protein that has been shown to associate with chromatin modifiers and transcription factors. In this study, we performed the first proteomic characterization of FKBP25 and found that it interacts with numerous ribosomal proteins, ribosomal processing factors, and a small selection of chromatin modifiers. In agreement with previous reports, we found that nucleolin is a major FKBP25-interacting protein and demonstrated that this interaction is dependent on rRNA. FKBP25 interacts with the immature large ribosomal subunit in nuclear extract but does not associate with mature ribosomes, implicating this FKBP's action in ribosome biogenesis. Despite engaging nascent 60S ribosomes, FKBP25 does not affect steady-state levels of rRNAs or its pre-rRNA intermediates. We conclude that FKBP25 is likely recruited to preribosomes to chaperone one of the protein components of the ribosome large subunit.

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Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 66%

Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 93%

Section: Fkbp25 Localizes To the Nucleus And Nucleolus And Associatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The prolyl isomerase, FKBP25, interacts with RNA-engaged nucleolin and the pre-60S ribosomal subunit

Gudavicius

Dilworth

Serpa

et al. 2014

RNA

View full text Add to dashboard Cite

show abstract

“…[3][4][5][6] Human FKBP25 is a 25 kDa protein which bears two domains linked by a long flexible loop. 7 Its C-terminal domain contains the well-conserved FK506 or rapamycin binding pocket, hence termed as the FK506 binding domain (FKBD).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the FK506 binding domain of human FKBP25 in complex with FK506

2016

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Human FKBP25 (hFKBP25) is a nuclear immunophilin and interacts with several nuclear proteins, hence involving in many nuclear events. Similar to other FKBPs, FK506 binding domain (FKBD) of hFKBP25 also binds to immunosuppressive drugs such as rapamycin and FK506, albeit with a lower affinity for the latter. The molecular basis underlying this difference in affinity could not be addressed due to the lack of the crystal structure of hFKBD25 in complex with FK506. Here, we report the crystal structure of hFKBD25 in complex with FK506 determined at 1.8 Å resolution and its comparison with the hFKBD25-rapamycin complex, bringing out the microheterogeneity in the mode of interaction of these drugs, which could possibly explain the lower affinity for FK506.

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C‐H…O hydrogen bonds in FK506‐binding protein–ligand interactions

Rajan

Baek

Yoon

2013

J of Molecular Recognition

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Hydrogen bonds are important interaction forces observed in protein structures. They can be classified as stronger or weaker depending on their energy, thereby reflecting on the type of donor. The contribution of weak hydrogen bonds is deemed as an important factor toward structure stability along with the stronger bonds. One such bond, the C-H…O type hydrogen bond, is shown to make a contribution in maintaining three dimensional structures of proteins. Apart from their presence within protein structures, the role of these bonds in protein-ligand interactions is also noteworthy. In this study, we present a statistical analysis on the presence of C-H…O hydrogen bonds observed between FKBPs and their cognate ligands. The FK506-binding proteins (FKBPs) carry peptidyl cis-trans isomerase activity apart from the immunosuppressive property by binding to the immunosuppressive drugs FK506 or rapamycin. Because the active site of FKBPs is lined up by many hydrophobic residues, we speculated that the prevalence of C-H…O hydrogen bonds will be considerable. In a total of 25 structures analyzed, a higher frequency of C-H…O hydrogen bonds is observed in comparison with the stronger hydrogen bonds. These C-H…O hydrogen bonds are dominated by a highly conserved donor, the C(α/β) of Val55 and an acceptor, the backbone oxygen of Glu54. Both these residues are positioned in the β4-α1 loop, whereas the other residues Tyr26, Phe36 and Phe99 with higher frequencies are lined up at the opposite face of the active site. These preferences could be implicated in FKBP pharmacophore models toward enhancing the ligand affinity. This study could be a prelude to studying other proteins with hydrophobic pockets to gain better insights into ligand recognition.

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FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53

Cited by 64 publications

References 15 publications

The prolyl isomerase, FKBP25, interacts with RNA-engaged nucleolin and the pre-60S ribosomal subunit

The prolyl isomerase, FKBP25, interacts with RNA-engaged nucleolin and the pre-60S ribosomal subunit

Crystal structure of the FK506 binding domain of human FKBP25 in complex with FK506

C‐H…O hydrogen bonds in FK506‐binding protein–ligand interactions

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