Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells

Cánovas, Begoña; Igea, Ana; Sartori, Alessandro A.; Gomis, Roger R.; Paull, Tanya T.; Isoda, Michitaka; Pérez‐Montoyo, Héctor; Serra, Violeta; González‐Suárez, Eva; Stracker, Travis H.; Nebreda, Ángel R.

doi:10.1016/j.ccell.2018.04.010

Cited by 76 publications

(77 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with equivalent experiments in which chromosome instability had been elicited by alternative methods such as mutations in genes involved in the spindle assembly checkpoint (bub3 and rod), spindle assembly (asp), chromatin condensation (orc2) or cytokinesis (dia) (Dekanty et al, 2012). Recently, the protein kinase p38a has been identified as a factor that limits chromosome instability by interfering with the activation of the ATR kinase and homologous recombination repair mechanisms in breast cancer cells (Canovas et al, 2018). Ultimately, depletion of p38a increases replication stress (Haahr et al, 2016).…”

Section: Tni Depletion Causes Cell Cytoskeletal Defects That Are Indesupporting

confidence: 87%

Troponin-I mediates the localization of selected apico-basal cell polarity signaling proteins

Casas‐Tintó

Ferrús

2019

Journal of Cell Science

View full text Add to dashboard Cite

Beyond its role in muscle contraction, Drosophila Troponin I (TnI; also known as Wings up A) is expressed in epithelial cells where it controls proliferation. TnI traffics between nucleus and cytoplasm through a sumoylation-dependent mechanism. We address here the role of TnI in the cytoplasm. TnI accumulates apically in epidermal cells and neuroblasts. TnI co-immunoprecipitates with Bazooka (also known as Par3) and Discs large (Dlg1, hereafter Dlg), two apico-basal polarity components. TnI depletion causes Baz and Dlg mislocalization; by contrast, the basolateral localization of Scribbled is not altered. In neuroblasts, TnI contributes to the polar localization of Miranda, while non-polar Dlg localization is not affected. Vertebrate phosphoinositide 3-kinase (PI3K) contributes to the apico-basal polarity of epithelia, but we find that Drosophila PI3K depletion alters neither the apical localization of TnI or Bazooka, nor the basal localization of Dlg. Nevertheless, overexpressing PI3K prevents the defects seen upon TnI depletion. TnI loss-of-function disrupts cytoskeletal β-Catenin, E-Cadherin and γ-Tubulin, and causes an increase in DNA damage, as revealed by analyzing γH2Av. We have previously shown that TnI depletion leads to apoptosis that can be suppressed by upregulating Sparc or downregulating Dronc. However, TnI-depleted cells expressing Sparc or downregulating Dronc, as well as those expressing p35 (also known as Cdk5α), that do not undergo apoptosis, still show DNA damage. This indicates that DNA damage is mechanistically independent of apoptosis induction. Thus, TnI binds certain apico-basal polarity signaling proteins in a cell type-dependent context, and this unveils a previously unsuspected diversity of mechanisms to allocate cell polarity factors.

show abstract

Section: Tni Depletion Causes Cell Cytoskeletal Defects That Are Indesupporting

confidence: 87%

Troponin-I mediates the localization of selected apico-basal cell polarity signaling proteins

Casas‐Tintó

Ferrús

2019

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Epifluorescence microscopy indicated colocalization of XPA and p38α when expressed in HEK293T cells (Figure c). Our results from fluorescence imaging, coimmunoprecipitation, and PLA imaging corroborate a UV‐induced physical association, whether direct or indirect, between p38α and XPA in HEK293T cells, consistent with a known role of this pathway in UV‐induced DNA damage control 39,45,46 …”

Section: Discussionsupporting

confidence: 82%

“…Thus, biotinylation of interactions by BioID2‐p38α is not likely impacted by nonphysiologic abundance of BioID2‐p38α fusion protein. Future studies may wish to perform BioID experiments in genetic knockout backgrounds, however, keeping in mind that genetic ablation (e.g., in the case of p38α ) may have impacts on cell division, physiology, and signaling networks 17,45,46 …”

Section: Discussionmentioning

confidence: 99%

Mapping p38α mitogen‐activated protein kinase signaling by proximity‐dependent labeling

2020

View full text Add to dashboard Cite

Mitogen-activated protein (MAP) kinase signaling is central to multiple cellular responses and processes. MAP kinase p38α is the best characterized member of the p38 MAP kinase family. Upstream factors and downstream targets of p38α have been identified in the past by conventional methods such as coimmunoprecipitation. However, a complete picture of its interaction partners and substrates in cells is lacking. Here, we employ a proximity-dependent labeling approach using biotinylation tagging to map the interactome of p38α in cultured 293T cells. Fusing the advanced biotin ligase BioID2 to the N-terminus of p38α, we used mass spectrometry to identify 37 biotin-labeled proteins that putatively interact with p38α. Gene ontology analysis confirms known upstream and downstream factors in the p38 MAP kinase cascade (e.g., MKK3, MAPKAPK2, TAB2, and c-jun). We furthermore identify a cluster of zinc finger (ZnF) domain-containing proteins that is significantly enriched among proximity-labeled interactors and is involved in gene transcription and DNA damage response. Fluorescence imaging and coimmunoprecipitation with overexpressed p38α in cells supports an interaction of p38α with ZnF protein XPA, a key factor in the DNA damage response, that is promoted by UV irradiation. These results define an extensive network of interactions of p38α in cells and new direct molecular targets of MAP kinase p38α in gene regulation and the DNA damage response. K E Y W O R D SBioID, biotinylation, interactome, MAP kinase, p38, p38α, protein-protein interaction, proximity-dependent labeling

show abstract

“…For example, p38 activity has been shown in both breast and lung cancer to promote chemotherapy resistance (Flem-Karlsen et al, 2019; Liu et al, 2016; Lu et al, 2018). Activation of p38 has also been linked to DNA repair (Canovas et al, 2018), which is also enriched in our models of enzalutamide resistance (Fig. 3B).…”

Section: Discussionmentioning

confidence: 74%

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Ware

Gupta

Eng

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryAdaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.

show abstract

Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells

Cited by 76 publications

References 57 publications

Troponin-I mediates the localization of selected apico-basal cell polarity signaling proteins

Troponin-I mediates the localization of selected apico-basal cell polarity signaling proteins

Mapping p38α mitogen‐activated protein kinase signaling by proximity‐dependent labeling

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Contact Info

Product

Resources

About