Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Guo, Qing; Fu, Weiming; Xie, Jun; Luo, Hong; Sells, Stephen F.; Geddes, James W.; Bondada, Vimala; Rangnekar, Vivek M.; Mattson, Mark P.

doi:10.1038/nm0898-957

Cited by 259 publications

(275 citation statements)

References 24 publications

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“…In our experiments, neither Dlk not Par-4 did induce apoptosis per se, in agreement with previous studies (KoÈ gel et al, 1998;Sells et al, 1997;Guo et al, 1998). Obviously, coexpression of both proteins can, under certain conditions, lead to apoptosis.…”

Section: Dlk/zip Kinase and Par-4 Cooperate In Inducing Apoptosissupporting

confidence: 93%

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

et al. 1999

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Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly associated with nuclear structures, it undergoes extensive autophosphorylation and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro. Moreover, it possesses a leucine zipper which mediates interaction with transcription factor ATF-4, therefore it was called ZIP kinase. We employed the yeast twohybrid system to identify interaction partners of Dlk that might serve as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk and Par-4 was con®rmed by GST pull-down experiments and kinase reactions in vitro and coexpression experiments in vivo. The interaction domain within Dlk was mapped to an arginine-rich region between residues 338 ± 417, rather than to the leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of Dlk from the nucleus to the cytoplasm, particularly to actin ®laments. These interactions provoked a dramatic reorganization of the cytoskeleton and morphological symptoms of apoptosis, thus suggesting a functional relationship between Dlk and Par-4 in the control of apoptosis.

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Section: Dlk/zip Kinase and Par-4 Cooperate In Inducing Apoptosissupporting

confidence: 93%

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

et al. 1999

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“…15 Whereas, increased PAR4 expression results in enhancement of the neurotoxic effects of amyloid beta peptide. 41 Although some cell specific responses have been noted during overexpression, collectively these findings document a role Our data demonstrate that NGF responses are amplified by the presence of excess atypical PKC, concomitant with amplification of NGF-induced activation of JNK. Although most work characterizing the JNK pathway has focused on cellular responses to stress, other growth factors such as insulin, that provide prosurvival signals, also lead to activation of JNK.…”

Section: Discussionsupporting

confidence: 58%

Overexpression of atypical PKC in PC12 cells enhances NGF-responsiveness and survival through an NF-κB dependent pathway

et al. 1999

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Removal of atypical PKC blocks NGF-induced differentiation of PC12 cells. 1 We now examine the consequences that overexpression of atypical PKCs had upon NGF responses. PC12 cells were stably transfected with either PKC-i or PKC-z. Overexpression of atypical PKCs markedly enhanced NGFinduced neurite outgrowth as well as enhanced NGFstimulated JNK kinase. Cotransfection of HA-JNK1 along with increasing concentrations of PKC-i, resulted in dosedependent phosphorylation of GST c-Jun (1 ± 79). NGF treatment of PC12 cells resulted in activation of NF-kB. In comparison, overexpression of atypical PKC-i was by itself sufficient to activate NF-kB and shift the kinetics of NGFinduced kB activity. Furthermore, transfection of full-length antisense PKC-i blocked basal and NGF-stimulated NF-kB. Differentiated and undifferentiated PC12 cells overexpressing atypical PKC-i were protected from serum deprivationinduced cell death. Collectively, these findings demonstrate that atypical PKC-i lies in a pathway that regulates NF-kB and contributes to both neurotrophin-mediated differentiation and survival signaling.

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“…Par-4 is a 38 kDa protein, initially identified as the product of a gene specifically upregulated in prostate tumor cells undergoing apoptosis (Sells et al, 1994), which has been shown to function as a transcriptional regulator with corepressor (Johnstone et al, 1996) or coactivator (Richard et al, 2001) properties for distinct isoforms of transcription factor WT1, the Wilms' tumor suppressor protein. Consistent with an important role of Par-4 in apoptosis, ectopic expression of Par-4 in NIH-3T3 cells (Diaz-Meco et al, 1996, neurons (Guo et al, 1998), prostate cancer and melanoma cells (Sells et al, 1997) has been found to sensitize these cells to apoptotic stimuli. In addition, downregulation of Par-4 is critical for ras-induced survival and tumor progression (Barradas et al, 1999) and suppression of Par-4 production by antisense technology prevents apoptosis in several systems (Sells et al, 1997), including different models of neurodegenerative disorders (Guo et al, 1998;Mattson et al, 1999), further emphasizing the critical role of Par-4 in apoptosis.…”

Section: Introductionmentioning

confidence: 53%

THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

et al. 2003

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Promyelocytic leukemia (PML) nuclear bodies (PML NBs) are discrete subnuclear domains organized by the promyelocytic leukemia protein PML, a tumor suppressor essential for multiple apoptotic pathways. We have recently described a novel family of cellular factors, the THAP proteins, characterized by the presence at their amino-terminus of an evolutionary conserved putative DNA-binding motif, designated THAP domain. Here, we report that THAP1 is a novel nuclear proapoptotic factor associated with PML NBs, which potentiates both serum withdrawal-and TNFa-induced apoptosis, and interacts with prostate-apoptosis-response-4 (Par-4), a well characterized proapoptotic factor, previously linked to prostate cancer and neurodegenerative diseases. We show that endogenous Par-4 colocalizes with ectopic THAP1 within PML NBs in primary endothelial cells and fibroblasts. In addition, we found that Par-4 is a component of PML NBs in blood vessels, a major site of PML expression in vivo. Finally, we investigated the role of the THAP domain in THAP1 activities and found that this putative DNA-binding domain is not required for Par-4 binding and localization within PML NBs, but is essential for THAP1 proapoptotic activity. Together, our results provide an unexpected link between a nuclear factor of the THAP family, the proapoptotic protein Par-4 and PML nuclear bodies.

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Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease

Cited by 259 publications

References 24 publications

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

Overexpression of atypical PKC in PC12 cells enhances NGF-responsiveness and survival through an NF-κB dependent pathway

THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies

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