The Transcriptional Coactivator Yes-Associated Protein Drives p73 Gene-Target Specificity in Response to DNA Damage

Strano, Sabrina; Monti, Olimpia; Pediconi, Natalia; Baccarini, Alessia; Fontemaggi, Giulia; Lapi, Eleonora; Mantovani, Fiamma; Damalas, Alexander; Citro, Gennaro; Sacchi, Ada; Sal, Giannino Del; Levrero, Massimo; Blandino, Giovanni

doi:10.1016/j.molcel.2005.07.010

Cited by 64 publications

(112 citation statements)

References 0 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…23 On the contrary, YAP expression in nucleus modulates the transcription of a variety of genes involved in cell growth and proliferation. 24 Moreover, positive YAP labeling was detected in 85.3% (29/34) of CIN-N, and 93.8% (30/32) of SCC. It was in consistence with previous reports that compared with benign tissues, YAP expression was elevated in a variety of human cancers.…”

Section: Discussionmentioning

confidence: 94%

Expression of Yes-Associated Protein in Cervical Squamous Epithelium Lesions

Xiao

Zheng

et al. 2014

International Journal of Gynecological Cancer

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 94%

Expression of Yes-Associated Protein in Cervical Squamous Epithelium Lesions

Xiao

Zheng

et al. 2014

International Journal of Gynecological Cancer

View full text Add to dashboard Cite

show abstract

“…In an attempt to elucidate the mechanism by which Hck inhibits p73 activity in a target specific manner, we tested the possible involvement of YAP, a molecule that binds to and selectively regulates p73 dependent transactivation [58,59]. YAP was first identified as the Src family kinase Yes, interacting protein [60].…”

Section: Resultsmentioning

confidence: 99%

Regulation of p73 by Hck through kinase-dependent and independent mechanisms

2007

View full text Add to dashboard Cite

Backgroundp73, a p53 family member is a transcription factor that plays a role in cell cycle, differentiation and apoptosis. p73 is regulated through post translational modifications and protein interactions. c-Abl is the only known tyrosine kinase that phosphorylates and activates p73. Here we have analyzed the role of Src family kinases, which are involved in diverse signaling pathways, in regulating p73.ResultsExogenously expressed as well as cellular Hck and p73 interact in vivo. In vitro binding assays show that SH3 domain of Hck interacts with p73. Co-expression of p73 with Hck or c-Src in mammalian cells resulted in tyrosine phosphorylation of p73. Using site directed mutational analysis, we determined that Tyr-28 was the major site of phosphorylation by Hck and c-Src, unlike c-Abl which phosphorylates Tyr-99. In a kinase dependent manner, Hck co-expression resulted in stabilization of p73 protein in the cytoplasm. Activation of Hck in HL-60 cells resulted in tyrosine phosphorylation of endogenous p73. Both exogenous and endogenous Hck localize to the nuclear as well as cytoplasmic compartment, just as does p73. Ectopically expressed Hck repressed the transcriptional activity of p73 as determined by promoter assays and semi-quantitative RT-PCR analysis of the p73 target, Ipaf and MDM2. SH3 domain- dependent function of Hck was required for its effect on p73 activity, which was also reflected in its ability to inhibit p73-mediated apoptosis. We also show that Hck interacts with Yes associated protein (YAP), a transcriptional co-activator of p73, and shRNA mediated knockdown of YAP protein reduces p73 induced Ipaf promoter activation.ConclusionWe have identified p73 as a novel substrate and interacting partner of Hck and show that it regulates p73 through mechanisms that are dependent on either catalytic activity or protein interaction domains. Hck-SH3 domain-mediated interactions play an important role in the inhibition of p73-dependent transcriptional activation of a target gene, Ipaf, as well as apoptosis.

show abstract

“…Interestingly, p73 expression is essential for the recruitment of YAP to PML-nuclear bodies following DNA damage as cells lacking p73 fail to do so. 41 …”

Section: Protein–protein Interactionsmentioning

confidence: 99%

“…41, 63, 64 Indeed, interaction of p73, YAP and p300 via PML is an important determinant of the selective activation of pro-apoptotic p73 targets in response to DNA damage. 41 p73 ubiquitination is also significantly reduced following its interaction with PML and localization to PML-nuclear bodies. 63 Apart from p38-mediated phosphorylation, c-Abl-mediated p73 phosphorylation also induces its sub-nuclear redistribution; following which, p73 translocates from the nucleocytoplasmic fraction to the nuclear matrix, potentially to become unavailable to ubiquitin ligases and escape proteasomal degradation.…”

Section: Modifications Leading To a Change In Subcellular Localizationmentioning

confidence: 99%

Regulation of p73 activity by post-translational modifications

et al. 2012

View full text Add to dashboard Cite

The transcription factor p73 is a member of the p53 family that can be expressed as at least 24 different isoforms with pro- or anti-apoptotic attributes. The TAp73 isoforms are expressed from an upstream promoter and are regarded as bona fide tumor suppressors; they can induce cell cycle arrest/apoptosis and protect against genomic instability. On the other hand, ΔNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TAp73 or p53 to block their transcriptional activities. Therefore, the ratio of TAp73 isoforms to ΔNp73 isoforms is critical for the quality of the response to a genomic insult and needs to be delicately regulated at both transcriptional and post-translational level. In this review, we will summarize the current knowledge on the post-translational regulatory pathways involved to keep p73 protein under control. A comprehensive understanding of p73 post-translational modifications will be extremely useful for the development of new strategies for treating and preventing cancer.

show abstract

The Transcriptional Coactivator Yes-Associated Protein Drives p73 Gene-Target Specificity in Response to DNA Damage

Abstract: In our recent article, there was an omission in the Acknowledgments section. The corrected text appears here.

Cited by 64 publications

References 0 publications

Expression of Yes-Associated Protein in Cervical Squamous Epithelium Lesions

Expression of Yes-Associated Protein in Cervical Squamous Epithelium Lesions

Regulation of p73 by Hck through kinase-dependent and independent mechanisms

Regulation of p73 activity by post-translational modifications

Contact Info

Product

Resources

About