p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

Madapura, Harsha S; Salamon, Dániel; Wiman, Klas G.; Laı́n, Sonia; Klein, George; Klein, Eva; Nagy, Noémi

doi:10.4161/cc.22810

Cited by 22 publications

(21 citation statements)

References 36 publications

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“…37 This results in significant changes in its functional properties as a transcription factor. [38][39][40][41][42][43] As a consequence of the p53 isoforms function as a transcription factor and its involvement in DNA damage, it is evident that the status of p53 plays a crucial role in cancer progression [44][45][46][47][48][49][50][51][52] as well in different physiological 2 and anticancer responses. 42 In fact, p53 is frequently mutated in cancer, resulting in novel "gain-of-function"effects.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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“…3,4 Here we have studied a mechanism for the p53 induction in these cells, and the consequences of high p53 levels. Our results demonstrate that the kinetics of cMyc expression and its downstream target p14ARF parallel T cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…4 Elevation of p53 has been shown to suppress cMyc transcription in different cell lines and by that cause cell cycle arrest. 20 Based on these findings, we asked whether p53 would suppress cMyc expression in activated T cells.…”

Section: High P53 Levels Downregulate Cmyc Expression In Activated T mentioning

confidence: 99%

“…3,4 Here we continued to study parameters related to the expression of p53 in proliferating T cells. Following activation with PHA, proliferation and cMyc expression were induced (Fig.…”

Section: Cmyc and P14arf Expression Are Induced In Activated T Cellsmentioning

confidence: 99%

“…We have previously shown that the tumor suppressor p53 contributes to this process through the induction of the pro-apoptotic protein SAP. 3,4 p53 regulates cell cycle progression and contributes to the maintenance of genome integrity. 5 Recent studies have also indicated that p53 suppresses cellular senescence through the inhibition of mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

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cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

et al. 2016

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Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells.

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