p63 and p73, members of the p53 gene family, transactivate PKCδ

Ponassi, Raffaella; Terrinoni, Alessandro; Chikh, Anissa; Rufini, Alessandro; Lena, Anna Maria; Sayan, Berna S.; Melino, Gerry; Candi, Eleonora

doi:10.1016/j.bcp.2006.07.031

Cited by 15 publications

(10 citation statements)

References 32 publications

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“…Further studies are needed to determine if PTPN14 and ING1 are direct transcriptional targets of p63. The functional REs in other target genes recently reported as uniquely regulated by p63 and not p53, such as Shh (Caserta et al, 2006), IKKa (Candi et al, 2006) and PKCg (Ponassi et al, 2006), further support our description of the p63 consensus DNA-binding site and its functional impact on target selectivity in the p53 family.…”

Section: Discussionsupporting

confidence: 87%

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

et al. 2007

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p53 and p63 belong to a family of sequence-specific transcription factors regulating key cellular processes. Differential composition of the p53 and p63 DNA-binding sites may contribute to distinct functions of these protein homologues. We used SELEX (systematic evolution of ligands by exponential enrichment) methodology to identify nucleic acid ligands for p63. We found that p63 bound preferentially to DNA fragments conforming to the 20 bp sequence 5 0 -RRRC(A/G)(A/T)GYYYRRRC(A/T) (C/T)GYYY-3 0 . Relative to the p53 consensus, the p63 consensus DNA-binding site (DBS) was more degenerate, particularly at positions 10 and 11, and was enriched for A/G at position 5 and C/T at position 16 of the consensus. The differences in DNA-binding site preferences between p63 and p53 influenced their ability to activate transcription from select response elements (REs) in cells. A computer algorithm, p63MH, was developed to find candidate p63-binding motifs on input sequences. We identified genes responsive to p63 regulation that contain functional p63 REs. Our results suggest that the sequence composition of REs could be one contributing factor to target gene discrimination between p63 and p53.

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Section: Discussionsupporting

confidence: 87%

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

et al. 2007

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“…Recent evidence supports a prominent role for caspase-dependent PKC␦ activation in oxidative stress-induced dopaminergic cell death in experimental models of PD because of a high expression of the kinase in nigrostriatal dopaminergic neurons (5,6,13). Despite extensive investigations of the molecular mechanisms of activation of PKC␦, relatively little information is available on the mechanisms that control PKC␦ expression at the transcriptional level (42)(43)(44)(45). Previous studies on the regulatory elements of the PKC␦ gene are all based on analysis of the 5Ј-flanking sequences upstream of the TSS; however, no attempt was made to examine the importance of the GC-rich domains in the first exon.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a huge distance, nearly 17 kb in human and 12 kb in rat and mouse, is revealed between the transcription start and translation start sites (40,41). To our knowledge, only a few studies have documented the functional elements in the PKC␦ promoter or the characteristics of the factors involved in the control of PKC␦ transcription (42)(43)(44)(45). In this study, we analyzed the mouse PKC␦ promoter to identify the transcriptional mechanisms underlying neuronal PKC␦ expression.…”

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confidence: 99%

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Jin

Kanthasamy

Anantharam

et al. 2011

Journal of Biological Chemistry

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We previously demonstrated that protein kinase C␦ (PKC␦; PKC delta) is an oxidative stress-sensitive kinase that plays a causal role in apoptotic cell death in neuronal cells. Although PKC␦ activation has been extensively studied, relatively little is known about the molecular mechanisms controlling PKC␦ expression. To characterize the regulation of PKC␦ expression, we cloned an ϳ2-kbp 5-promoter segment of the mouse Prkcd gene. Deletion analysis indicated that the noncoding exon 1 region contained multiple Sp sites, including four GC boxes and one CACCC box, which directed the highest levels of transcription in neuronal cells. In addition, an upstream regulatory region containing adjacent repressive and anti-repressive elements with opposing regulatory activities was identified within the region ؊712 to ؊560. PKC represents a large family of at least 12 serine/threonine kinases that participate in a wide variety of cellular events, including proliferation, cell cycle progression, differentiation, and apoptosis (1). Based on their structure and substrate requirements, PKC isoforms are divided into the following three groups: conventional PKCs (␣, ␤I, ␤II, and ␥), novel PKCs (␦, ⑀, , and ), and atypical PKCs ( and /). As a novel PKC, PKC␦ has been recognized as a key pro-apoptotic effector in various cell types (2, 3). The role of PKC␦ in nervous system function is beginning to emerge, and recent studies show that PKC␦ plays a role in regulation of receptor and channel activity, differentiation, migration, and apoptosis (4). In addition to lipid-mediated activation and phosphorylation activation, a new pathway of PKC␦ activation, proteolytic cleavage, was discovered recently. Previously, we showed that PKC␦ is an oxidative stress-sensitive kinase and that persistent activation of PKC␦ by caspase-3-mediated proteolytic cleavage is a key mediator in oxidative stress-induced dopaminergic neurodegeneration (5-9). Alternatively, pharmacological inhibition of PKC␦ and depletion of PKC␦ by siRNA are each sufficient to prevent dopaminergic neurodegeneration in cell culture and animal models of Parkinson disease (10 -12). We also showed that PKC␦ negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase 2A activity in dopaminergic neurons (13). An elevated striatal dopamine level was observed in PKC␦ knock-out mice as compared with wild-type mice, further demonstrating a key role of the kinase in the nigrostriatal dopaminergic function (13). In addition, increased PKC␦ activity, caused by aberrant expression of PKC␦, has been implicated in disease conditions, such as ischemia/hypoxia (14 -17) and cancer (18 -28). Therefore, an understanding of the molecular mechanisms that control the amount and activity of PKC␦ is of physiological and pathophysiological interest.PKC␦ is ubiquitously expressed although the expression pattern is varied and complex (29 -32). Evidence suggests that diverse stimuli can induce PKC␦ expression (33)(34)(35)(37)(38)(39), but the detailed mechanisms...

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“…The ⌬N isoforms are expressed from an intronic promoter and therefore lack the TA domain. However, the presence of a second TA domain between residues 410 and 512 (TA2) confers transcriptional activity on at least some ⌬Np63 isoforms (4)(5)(6)(7).…”

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confidence: 99%

Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis

Sayan

Yang

et al. 2007

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

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p63 is a p53-related transcription factor. Utilization of two different promoters and alternative splicing at the C terminus lead to generation of six isoforms. The ␣ isoforms of TAp63 and ⌬Np63 contain a transactivation-inhibitory (TI) domain at the C termini, which can bind to the transactivation (TA) domain and inhibit its transcriptional activity. Consequently, TAp63␣ can directly inhibit its activity through an intramolecular interaction; similarly, ⌬Np63␣ can inhibit the activity of the active TAp63 isoforms through an intermolecular interaction. In this work, we demonstrate that after induction of apoptosis, the TI domain of the p63␣ isoforms is cleaved by activated caspases. Cleavage of ⌬Np63␣ relieves its inhibitory effect on the transcriptionally active p63 proteins, and the cleavage of TAp63␣ results in production of a TAp63 protein with enhanced transcriptional activity. In agreement with these data, generation of the N-terminal TAp63 fragment has a role in apoptosis because stable cell lines expressing wild-type TAp63 are more sensitive to apoptosis compared with cells expressing the noncleavable mutant. We also used a model system in which TAp63 expression was induced by trichostatin-A treatment in HCT116 cells. Trichostatin-A sensitized these cells to apoptosis, and this sensitization was associated with cleavage of up-regulated p63.cancer ͉ p53 ͉ transcription ͉ histone deacetylase inhibitor ͉ trichostatin A

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p63 and p73, members of the p53 gene family, transactivate PKCδ

Cited by 15 publications

References 32 publications

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis

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