Selective Inactivation of Parvulin-Like Peptidyl-Prolyl <i>cis/trans</i> Isomerases by Juglone

Hennig, Lars; Christner, Claudia; Kipping, Marc; Schelbert, Birte; Rücknagel, Karl Peter; Grabley, Susanne; Küllertz, Gerhard; Fischer, Gunter

doi:10.1021/bi973162p

Cited by 296 publications

(297 citation statements)

References 33 publications

Supporting

Mentioning

282

Contrasting

Unclassified

Order By: Relevance

“…Neither CsA nor FK506 inhibited this activity (Table II), indicating that the PrsA preparations were not contaminated with cyclophilins or FKBP-type PPIases. They were also free of the E. coli parvulin, since juglone did not affect the activity (31). These results suggest that PrsA is a PPIase.…”

Section: The N-terminal C-terminal and Parvulin-like Regions Arementioning

confidence: 74%

“…Cyclosporin A (CsA, Sigma-Aldrich) and FK506 (Calbiochem) were used at 5 M concentrations to inhibit PPIase activities of putative contaminating cyclophilins and FKBP-type PPIases in the PrsA preparations, respectively. Juglone (Sigma-Aldrich), which is an inhibitor of numerous parvulins, was used at 7 M concentrations as described (31). Cyclophilin, which was used as a positive control, was from calf thymus and was purchased from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Structure-Function Analysis of PrsA Reveals Roles for the Parvulin-like and Flanking N- and C-terminal Domains in Protein Folding and Secretion in Bacillus subtilis

Vitikainen

Lappalainen

Seppälä

et al. 2004

Journal of Biological Chemistry

118

View full text Add to dashboard Cite

The PrsA protein of Bacillus subtilis is an essential membrane-bound lipoprotein that is assumed to assist post-translocational folding of exported proteins and stabilize them in the compartment between the cytoplasmic membrane and cell wall. This folding activity is consistent with the homology of a segment of PrsA with parvulin-type peptidyl-prolyl cis/trans isomerases (PPIase). In this study, molecular modeling showed that the parvulin-like region can adopt a parvulin-type fold with structurally conserved active site residues. PrsA exhibits PPIase activity in a manner dependent on the parvulin-like domain. We constructed deletion, peptide insertion, and amino acid substitution mutations and demonstrated that the parvulin-like domain as well as flanking N-and C-terminal domains are essential for in vivo PrsA function in protein secretion and growth. Surprisingly, none of the predicted active site residues of the parvulin-like domain was essential for growth and protein secretion, although several active site mutations reduced or abolished the PPIase activity or the ability of PrsA to catalyze proline-limited protein folding in vitro. Our results indicate that PrsA is a PPIase, but the essential role in vivo seems to depend on some non-PPIase activity of both the parvulin-like and flanking domains.

show abstract

Section: The N-terminal C-terminal and Parvulin-like Regions Arementioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Structure-Function Analysis of PrsA Reveals Roles for the Parvulin-like and Flanking N- and C-terminal Domains in Protein Folding and Secretion in Bacillus subtilis

Vitikainen

Lappalainen

Seppälä

et al. 2004

Journal of Biological Chemistry

118

View full text Add to dashboard Cite

show abstract

“…Different research groups are currently developing Pin1 small-molecule inhibitors, whose efficacy in anticancer therapy should be tested in vivo. [32][33][34] Furthermore, we have found that the other two members of the pocket protein family, namely p130/pRb2 and p107, are substrates of Pin1. As in T98G cells the Pin1 and pRb interaction plays a major role in the G1/S cell cycle control, it would be interesting to analyze Pin1, pRb2/p130, and p107 in other cancer cells or other physiological processes.…”

Section: Discussionmentioning

confidence: 89%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

View full text Add to dashboard Cite

Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

show abstract

“…The compound covalently inactivates a cysteine residue in the active site of Pin1 isomerase (39). Intraperitoneal juglone injection was done every other day after a booster injection of CII and continued for 9 days (total four times).…”

Section: Juglone Inhibits Ra Progress In Cii-inducible Dba/1j Mice Anmentioning

confidence: 99%

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

Jeong

Pokharel

Lim

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints and subsequent destruction of cartilage and bone. Inflammatory mediators such as PGs and proinflammatory cytokines contribute to RA progress. Pin1, a peptidyl prolyl isomerase, plays important pathophysiological roles in several diseases, including cancer and neurodegeneration. We found that both Pin1 and cyclooxygenase-2 (COX-2) were highly expressed in ankle tissues of type II collagen-induced RA mice. HTB-94 cells overexpressing Pin1 and primary cultured human chondrocytes showed increased basal expression of proinflammatory proteins (COX-2, inducible NO synthase, TNF-α, and IL-1β). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-κB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-κB, CREB, and C/EBP were consistently activated in chondrocytes overexpressing Pin1. Treatment of RA mice with juglone, a chemical inhibitor of Pin1, significantly reduced RA progress and COX-2 expression in the ankle tissues. Moreover, juglone dose dependently decreased the basal COX-2 expression in primary cultured chondrocytes from RA patients. These results demonstrate that Pin1 induction during RA progress stimulates proinflammatory protein expression by activating NF-κB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.

show abstract

Selective Inactivation of Parvulin-Like Peptidyl-Prolyl cis/trans Isomerases by Juglone

Cited by 296 publications

References 33 publications

Structure-Function Analysis of PrsA Reveals Roles for the Parvulin-like and Flanking N- and C-terminal Domains in Protein Folding and Secretion in Bacillus subtilis

Structure-Function Analysis of PrsA Reveals Roles for the Parvulin-like and Flanking N- and C-terminal Domains in Protein Folding and Secretion in Bacillus subtilis

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

Contact Info

Product

Resources

About