Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Darnell, Grant A.; Antalis, Toni M.; Johnstone, Ricky W.; Stringer, Brett W.; Ogbourne, Steven M.; Harrich, David; Suhrbier, Andreas

doi:10.1128/mcb.23.18.6520-6532.2003

Cited by 65 publications

(105 citation statements)

References 48 publications

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“…PAI-2 A380 also lost its binding to HSP90/Beclin 1, resulting in loss of autophagy induction in response to LPS. However, residue 380 of PAI-2 is crucial for retinoblastoma stability and protection from TNF-induced apoptosis (12,32) . PAI-2 decreases IL-1β, but not TNF, production and cell death in response to E. coli infection.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, PAI-2 has been associated with newly identified uPA-independent biological functions, probably through targeting an as yet uncharacterized intracellular molecule (11). In addition, PAI-2 is one of the major molecules up-regulated in macrophages in response to TLR4 activators or inflammatory mediators, suggesting its function in the regulation of innate immunity (12,13).…”

mentioning

confidence: 99%

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TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

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The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

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“…However, it has been recently reported that in Hela and in Jurkat cells PAI-2 expression could result in post-transcriptional recovery of the retinoblastoma protein Rb, and that PAI-2 could inhibit Rb degradation, suggesting an intriguing intranuclear role of PAI-2. 11 Under physiological conditions, the expression of PAI-2 gene is maintained at low to undetectable levels in several cells. 3 However, it has been reported that a wide variety of factors, such as lipopolysaccharide, phorbol myristate acetate, tumor necrosis factor-a, interleukin-1, can modulate PAI-2 expression in different cell types.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

et al. 2006

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Extracellular plasminogen activator inhibitor type-2 (PAI-2) is a potent inhibitor of urokinase-type plasminogen activator (u-PA) and also acts as a multifunctional protein. However, the biological activity of intracellular PAI-2, as well as its intracellular targets, until now remain an enigma. Here, we show that pRb2/p130 and Rb1/p105, but not p107, interact with PAI-2 in both the cytoplasm and nucleus of normal primary human corneal and conjunctival epithelial cells. We provided the first in vivo evidence that a specific fragment of the PAI-2 promoter is bound simultaneously by pRb2/ p130, PAI-2, E2F5, histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1), and histone methyltransferase (SUV39H1), in normal primary human corneal epithelial cells, and by pRb2/p130, PAI-2, E2F5, HDAC1, and DNMT1, in normal primary human conjunctiva epithelial cells. Our results strongly indicate a physiological interaction between pRb family members and PAI-2, suggesting the hypothesis that pRb2/p130 and PAI-2 may cooperate in modulating PAI-2 gene expression by chromatin remodeling, in normal corneal and conjunctival cells.

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“…Recently, the threedimensional structure of RB C-region in complex with an E2F/DP heterodimer has been reported (Rubin et al, 2005). The RB C-region also interacts with a Pro, Glu, Asn, Phe ('PENF') peptide motif found in several cellular proteins (Darnell et al, 2003), and a binding site for cyclin-dependent protein kinases (Adams et al, 1999). A majority of the RB-interacting proteins are regulators of transcription (Morris and Dyson, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent studies of RB C-region binding partners have led to the identification of a 'PENF' motif that is present in Abl, cPLA2, BRCA1, and several other cellular proteins as the motif recognized by the RB 'C-pocket' (Darnell et al, 2003). The 'PENF' motif is present in the Abl kinase domain, at the C-helix of the kinase N-lobe.…”

Section: Introductionmentioning

confidence: 99%

Reduction of apoptosis in Rb-deficient embryos via Abl knockout

2006

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The retinoblastoma protein RB regulates cell proliferation, differentiation and apoptosis. Homozygous knockout of Rb in mice causes embryonic lethality owing to placental defects that result in excessive apoptosis. RB binds to a number of cellular proteins including the nuclear Abl protein and inhibits its tyrosine kinase activity. Ex vivo experiments have shown that genotoxic or inflammatory stress can activate Abl kinase to stimulate apoptosis. Employing the Rb-null embryos as an in vivo model of apoptosis, we have shown that the genetic ablation of Abl can reduce apoptosis in the developing central nervous system and the embryonic liver. These results are consistent with the inhibitory interaction between RB and Abl, and provide in vivo evidence for the proapoptotic function of Abl.

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Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Abstract: Plasminogen activator inhibitor-2 (PAI-2

Cited by 65 publications

References 48 publications

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

Reduction of apoptosis in Rb-deficient embryos via Abl knockout

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