Regulation of p73 activity by post-translational modifications

Conforti, Franco; Sayan, Emre; Sreekumar, Rahul; Sayan, Berna S.

doi:10.1038/cddis.2012.27

Cited by 62 publications

(58 citation statements)

References 101 publications

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“…aging, [27][28][29] and metabolism 27 through the regulation of gene [30][31][32] and microRNA expression. Mice deficient in p73 display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus.…”

Section: Introductionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis

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Section: Introductionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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“…Both in cancer progression, metastasis, and in physiological development, all members of the family interact and regulate each other. 117,118 This is, for example, evident in epidermis, 119 as well as in DNA damage response. 120 The p53 protein is highly conserved in its structure from C. elegans, D. melanogaster to H. sapiens.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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“…24 Regulation of the activity of members of the p53 protein family gets further complicated by the formation of oligomers that can include isoforms lacking a transactivation domain exerting a dominant-negative effect on the respective TA-isoform. 14,25,26 Furthermore, even mixed hetero-oligomers between p63 and p73 are possible, making oligomerization an important regulatory mechanism.…”

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confidence: 99%

Analysis of the oligomeric state and transactivation potential of TAp73α

et al. 2013

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The proteins p73 and p63 are members of the p53 protein family and are involved in important developmental processes. Their high sequence identity with the tumor suppressor p53 has suggested that they act as tumor suppressors as well. While p63 has a crucial role in the maintenance of epithelial stem cells and in the quality control of oocytes without a clear role as a tumor suppressor, p73 0 s tumor suppressor activity is well documented. In a recent study we have shown that the transcriptional activity of TAp63a, the isoform responsible for the quality control in oocytes, is regulated by its oligomeric state. The protein forms an inactive, dimeric and compact conformation in resting oocytes, while the detection of DNA damage leads to the formation of an active, tetrameric and open conformation. p73 shows a high sequence identity to p63, including those domains that are crucial in stabilizing its inactive state, thus suggesting that p73's activity might be regulated by its oligomeric state as well. Here, we have investigated the oligomeric state of TAp73a by size exclusion chromatography and detailed domain interaction mapping, and show that in contrast to p63, TAp73a is a constitutive open tetramer. However, its transactivation potential depends on the cellular background and the promoter context. These results imply that the regulation of p73 0 s transcriptional activity might be more closely related to p53 than to p63.

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Regulation of p73 activity by post-translational modifications

Cited by 62 publications

References 101 publications

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Molecular dynamics of the full-length p53 monomer

Analysis of the oligomeric state and transactivation potential of TAp73α

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