Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Dieck, Jan van; Teufel, Daniel P.; Jaulent, Agnès M.; Fernández-Fernández, Marı́a Rosario; Rutherford, Trevor J.; Wyslouch-Cieszynska, Alexandra; Fersht, Alan R.

doi:10.1016/j.jmb.2009.10.002

Cited by 64 publications

(90 citation statements)

References 48 publications

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“…Such an interaction may occur by S100B destabilizing p53 and/or preventing the formation of p53 oligomers, as observed previously (23,(31)(32)(33) and by NMR from our group (data not shown). Additionally, it is possible that elevated S100B blocks covalent modification of p53 (i.e.…”

Section: Discussionsupporting

confidence: 79%

“…1-3, supplemental Figs. 2S and 3S), and previously (26,27), was likely the result of a direct S100B-p53 protein-protein interaction detected in vitro (23,24,26,28,(31)(32)(33) and via coimmunoprecipitation from C8146A cells (26).…”

Section: Inhibiting S100b Expression (Via Sirna S100b ) Sensitizes Humentioning

confidence: 62%

“…However, studies from the Fersht group have begun to identify the source of these discrepancies, because they have discovered that several S100 proteins can interact with p53 and that these S100 proteins interact with the transactivation and/or the C terminus of p53 with affinities that vary by as much as an order of magnitude for two specific sites on p53 (31)(32)(33)76). With this information in mind, it now becomes important to know the relative amount of each member of the S100 protein family member within a particular cell type, because their abundance could result in different functional outcomes with regard to p53 activity.…”

Section: Discussionmentioning

confidence: 99%

“…As pointed out by Fersht and colleagues (31)(32)(33), several S100 proteins bind both the transactivation domain of p53 as well as the C terminus of p53 with varying affinities, and these S100-p53 protein-protein interactions are regulated by posttranslational modifications (i.e. phosphorylation and acetylation) (28,33). Such data provide additional explanations for why the effects of S100 proteins on p53 may be different in various cell types particularly, because S100 proteins themselves are cell specifically distributed (13).…”

mentioning

confidence: 88%

“…Such S100B-dependent effects on p53 are cell-specific, because there is also evidence that S100B rescued a temperature-sensitive p53val135 mutant in fibroblast cell lines (25,29,30). As pointed out by Fersht and colleagues (31)(32)(33), several S100 proteins bind both the transactivation domain of p53 as well as the C terminus of p53 with varying affinities, and these S100-p53 protein-protein interactions are regulated by posttranslational modifications (i.e. phosphorylation and acetylation) (28,33).…”

mentioning

confidence: 97%

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The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

Lin

Yang

Wilder

et al. 2010

Journal of Biological Chemistry

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The S100B-p53 protein complex was discovered in C8146A malignant melanoma, but the consequences of this interaction required further study. When S100B expression was inhibited in C8146As by siRNA (siRNA S100B ), wt p53 mRNA levels were unchanged, but p53 protein, phosphorylated p53, and p53 gene products (i.e. p21 and PIDD) were increased. siRNA S100B transfections also restored p53-dependent apoptosis in C8146As as judged by poly(ADP-ribose) polymerase cleavage, DNA ladder formation, caspase 3 and 8 activation, and aggregation of the Fas death receptor (؉UV); whereas, siRNA S100B had no effect in SK-MEL-28 cells containing elevated S100B and inactive p53 (p53R145L mutant). siRNA S100B -mediated apoptosis was independent of the mitochondria, because no changes were observed in mitochondrial membrane potential, cytochrome c release, caspase 9 activation, or ratios of pro-and anti-apoptotic proteins (BAX, Bcl-2, and Bcl-X L ). As expected, cells lacking S100B (LOX-IM VI) were not affected by siRNA S100B , and introduction of S100B reduced their UV-induced apoptosis activity by 7-fold, further demonstrating that S100B inhibits apoptosis activities in p53-containing cells. In other wild-type p53 cells (i.e. C8146A, UACC-2571, and UACC-62), S100B was found to contribute to cell survival after UV treatment, and for C8146As, the decrease in survival after siRNA S100B transfection (؉UV) could be reversed by the p53 inhibitor, pifithrin-␣. In summary, reducing S100B expression with siRNA was sufficient to activate p53, its transcriptional activation activities, and p53-dependent apoptosis pathway(s) in melanoma involving the Fas death receptor and perhaps PIDD. Thus, a well known marker for malignant melanoma, S100B, likely contributes to cancer progression by down-regulating the tumor suppressor protein, p53.In addition to regulating numerous genes and pathways involved in cell cycle control (1), the tumor suppressor protein, p53, is an important component for inducing apoptosis (2-4). The p53 protein activates the transcription of pro-apoptotic factors (BAX, Bak, Fas/APO-1, PIDD, etc.) as well as suppresses the transcription of anti-apoptotic genes (Bcl-2, Bcl-X L , etc.) (5, 6). In addition, p53 itself up-regulates apoptosis, without transcription activation, by directly localizing to mitochondria following DNA damage and interacting with anti-apoptotic proteins such as Bcl-X L to free pro-apoptotic proteins like BAX (2, 3, 5, 7). Under stress, the p53 protein can also contribute to apoptosis by facilitating the transport of death receptors such as Fas/APO-1 and/or Killer/DR5 from cytoplasmic stores to the cell surface as required for programmed cell death (5, 8). Although, it is now clear that p53-dependent pathways of apoptosis are numerous and are regulated in a cell-type and signalspecific manner (5).Apoptosis is initiated by a variety of stimuli, including withdrawal of growth factors, activation of specific receptors, such as Fas antigen and TNF receptor, and/or by exposure to UV radiation, ␥ irradiation, DNA-da...

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Section: Discussionsupporting

confidence: 79%

Section: Inhibiting S100b Expression (Via Sirna S100b ) Sensitizes Humentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

mentioning

confidence: 97%

See 3 more Smart Citations

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

Lin

Yang

Wilder

et al. 2010

Journal of Biological Chemistry

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Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

et al. 2020

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Conformationally flexible protein complexes represent a major challenge for structural and dynamical studies. We present herein a method based on a hybrid NMR/MD approach to characterize the complex formed between the disordered p53TAD 1-60 and the metastasis-associated S100A4. Disorder-toorder transitions of both TAD1 and TAD2 subdomains upon interaction is detected. Still, p53TAD 1-60 remains highly flexible in the bound form, with residues L26, M40, and W53 being anchored to identical hydrophobic pockets of the S100A4 monomer chains. In the resulting "fuzzy" complex, the clamplike binding of p53TAD 1-60 relies on specific hydrophobic anchors and on the existence of extended flexible segments. Our results demonstrate that structural and dynamical NMR parameters (cumulative Δδ, SSP, temperature coefficients, relaxation time, hetNOE) combined with MD simulations can be used to build a structural model even if, due to high flexibility, the classical solution structure calculation is not possible.

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Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

Ермаков

Daks

Fedorova

et al. 2018

Cell Biology International

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Ca -mediated signaling is widely spread in nature and plays critical role in the individual development of various organisms ranging from microorganisms to mammals. In vertebrates, Ca is involved in important developmental events: fertilization, body plan establishment, and organogenesis. The two later events are defined by embryonic stem cells (ESCs). ESCs are capable of self-renewal and are pluripotent by nature, that is, can give rise to all types of cells that make up the body. Given the paramount importance of Ca signalization in the development, it is therefore not surprising this process also plays role in the biology of stem cells. In this review, we scrutinize the published experimental data on the role of Ca ions in embryonic stem cells self-renewal and pluripotency. In line with this, we also discuss possible mechanisms of p53 inhibition as a major hindrance to self-renewal of ESCs. Finally, we argue about the role of G-protein-coupled receptors (GPCRs), the largest family of heteromeric transmembrane receptors, and GPCR-mediated signalization in stem cells, and propose the role for the GPCR-G-protein-PLC-Ca -downstream signaling pathway in the regulation of pluripotency of both mouse and human ESCs.

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Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Cited by 64 publications

References 48 publications

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

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Posttranslational Modifications Affect the Interaction of S100 Proteins with Tumor Suppressor p53

Cited by 64 publications

References 48 publications

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

The Calcium-binding Protein S100B Down-regulates p53 and Apoptosis in Malignant Melanoma

Tumor‐Suppressor p53TAD1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

Ca2+‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells

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Tumor‐Suppressor p53TAD^1–60 Forms a Fuzzy Complex with Metastasis‐Associated S100A4: Structural Insights and Dynamics by an NMR/MD Approach

Ca²⁺‐depended signaling pathways regulate self‐renewal and pluripotency of stem cells