Dipeptidyl peptidase 8 and 9 - guilty by association?

Pitman, Melissa R.; Sulda, Melanie; Kuss, Bryone J.; Abbott, Catherine A.

doi:10.2741/3476

Cited by 23 publications

(13 citation statements)

References 99 publications

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“…Thus, the relative contribution of particular DPPs may change significantly in the tumor tissue, as compared with the isolated tumor cells. Moreover, in the tumor microenvironment, DPPs may acquire new functions dependent on interactions with host cells, extracellular matrix, and stroma-derived proteolytic substrates, such as regulation of cell invasiveness and anti-tumor immune response (19,21,45).…”

Section: Discussionmentioning

confidence: 99%

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Dipeptidyl Peptidases as Survival Factors in Ewing Sarcoma Family of Tumors

Tilan

Everhart

et al. 2011

Journal of Biological Chemistry

114

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Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY 3-36 , not active at Y1Rs. We have shown that NPYinduced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosisinducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors.

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Section: Discussionmentioning

confidence: 99%

“…All of these enzymes have been implicated in regulation of growth and metastases of many tumors (15,18,19). The increasing interest in these potential therapeutic targets led to the development of numerous DPP inhibitors.…”

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confidence: 99%

Dipeptidyl Peptidases as Survival Factors in Ewing Sarcoma Family of Tumors

Tilan

Everhart

et al. 2011

Journal of Biological Chemistry

114

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“…DPP8 and DPP9 are widely distributed (25, 26). Although definitive biological functions are yet to be identified, they have been implicated in a range of diseases that include diabetes, cancer, arthritis, and asthma (27, 28). There is evidence for their involvement in T cell activation, cell cycle progression, antigen presentation, and inhibition of these two enzymes results in severe toxicity and pathology in rats and dogs (29–32).…”

Section: Introductionmentioning

confidence: 99%

Induced-fit Mechanism for Prolyl Endopeptidase

Chen

Davies

et al. 2010

Journal of Biological Chemistry

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Prolyl peptidases cleave proteins at proline residues and are of importance for cancer, neurological function, and type II diabetes. Prolyl endopeptidase (PEP) cleaves neuropeptides and is a drug target for neuropsychiatric diseases such as post-traumatic stress disorder, depression, and schizophrenia. Previous structural analyses showing little differences between native and substrate-bound structures have suggested a lock-and-key catalytic mechanism. We now directly demonstrate from seven structures of Aeromonus punctata PEP that the mechanism is instead induced fit: the native enzyme exists in a conformationally flexible opened state with a large interdomain opening between the β-propeller and α/β-hydrolase domains; addition of substrate to preformed native crystals induces a large scale conformational change into a closed state with induced-fit adjustments of the active site, and inhibition of this conformational change prevents substrate binding. Absolute sequence conservation among 28 orthologs of residues at the active site and critical residues at the interdomain interface indicates that this mechanism is conserved in all PEPs. This finding has immediate implications for the use of conformationally targeted drug design to improve specificity of inhibition against this family of proline-specific serine proteases.

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“…We and others have recently demonstrated that novel inhibitors of dipeptidyl peptidase (DP)‐IV activity can partially ameliorate the effects of DSS‐induced colitis, reducing colonic myeloperoxidase (MPO) activity as well as improving crypt area and crypt cell proliferation (Bank et al, 2006, 2008; Yazbeck et al, 2008, 2010). DPIV is a ubiquitously expressed trans‐membrane ectopeptidase that possesses a unique catalytic activity, cleaving N‐terminal dipeptides from polypeptides with a penultimate proline or alanine residue (Chen et al, 2004; Pitman et al, 2009). Previous studies have determined a high and evenly distributed DPIV activity along the brush border of the small intestine (Miura et al, 1983; Erickson et al, 1992).…”

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confidence: 99%

Biochemical and histological changes in the small intestine of mice with dextran sulfate sodium colitis

et al. 2011

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The dextran sulfate sodium (DSS) model of colitis has been commonly utilized in mice to assess novel treatments for ulcerative colitis. Recent studies have indicated that morphological and biochemical changes extend to the small intestine (SI). This study aimed to characterize histological and biochemical changes in the SI during DSS colitis in wild-type (WT) and DPIV knock-out (DPIV(-/-) ) mice treated with saline or the DPIV inhibitors, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Groups (n = 10) of DPIV(-/-) and WT mice were orally gavaged twice daily with saline, Ile-Pyrr-(2-CN)*TFA or Ile-Thia. Mice consumed 2% DSS in drinking water for 6 days to induce colitis. Small intestinal tissue was assessed for histological changes, sucrase, and DPIV activity and neutrophil infiltration. Jejunal villus length was increased in all groups after 6 days DSS consumption (P < 0.05). Jejunal DPIV activity was significantly lower by 35% in WT mice receiving Ile-Pyrr-(2-CN)*TFA compared to saline controls. Jejunal MPO activity was significantly increased in the WT + saline and DPIV(-/-) + saline groups following DSS consumption, compared to WT and DPIV(-/-) controls at day 0. Increased sucrase activity was apparent at day 0 in DPIV(-/-) compared to WT mice (P < 0.05). We conclude that DSS-induced damage is not restricted to the colon, but also extends to the small intestine. Furthermore, reduced or absent DPIV activity resulted in functional adaptations to brush border enzyme activity. DPIV inhibitors are now a recognized therapy for type-II diabetes. The work presented here highlights the need to delineate any long-term effects of DPIV inhibitors on SI function, to further validate their safety and tolerability.

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Dipeptidyl peptidase 8 and 9 - guilty by association?

Cited by 23 publications

References 99 publications

Dipeptidyl Peptidases as Survival Factors in Ewing Sarcoma Family of Tumors

Dipeptidyl Peptidases as Survival Factors in Ewing Sarcoma Family of Tumors

Induced-fit Mechanism for Prolyl Endopeptidase

Biochemical and histological changes in the small intestine of mice with dextran sulfate sodium colitis

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