p38γ is essential for cell cycle progression and liver tumorigenesis

Tomás-Loba, Antonia; Manieri, Elisa; González‐Terán, Bárbara; Mora, Alfonso; Leiva‐Vega, Luis; Santamans, Ayelén M; Romero-Becerra, Rafael; Rodrı́guez, Elena; Pintor-Chocano, Aranzazú; Feixas, Ferran; López, Juan Antonio; Caballero, Beatriz; Trakala, Marianna; Blanco, Óscar; Torres, Jorge; Hernández‐Cosido, Lourdes; Montalvo-Romeral, Valle; Matesanz, Nuria; Roche-Molina, Marta; Bernal, Juan A.; Mischo, Hannah E.; León, Marta; Caballero, Ainoa; Miranda‐Saavedra, Diego; Ruíz-Cabello, Jesús; Nevzorova, Yulia A.; Cubero, Francisco Javier; Bravo, Jerónimo; Vázquez, Jesús; Malumbres, Marcos; Marcos, Miguel; Osuna, Sílvia; Sabio, Guadalupe

doi:10.1038/s41586-019-1112-8

Cited by 82 publications

(85 citation statements)

References 28 publications

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“…Moreover, p38γ is essential in liver tumorigenesis; in mouse hepatocytes, p38γ induces proliferation after partial hepatectomy by promoting the phosphorylation of retinoblastoma (RB) tumor suppressor protein at known CDK target residues. Indeed, lack of p38γ or treatment with the p38γ inhibitor protects against the chemically induced formation of liver tumors [98]. Such isoform specificity is also observed in other contexts.…”

Section: P38 Mapk As a Tumor Promotermentioning

confidence: 84%

The p38 Pathway: From Biology to Cancer Therapy

Martínez-Limón

Joaquin

Caballero

et al. 2020

IJMS

272

199

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The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. In this review, we provide an extensive description of the main biological functions of p38 and focus on recent studies that have addressed its role in cancer. Furthermore, we provide an updated overview of therapeutic strategies targeting p38 in cancer and promising alternatives currently being explored.

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Section: P38 Mapk As a Tumor Promotermentioning

confidence: 84%

The p38 Pathway: From Biology to Cancer Therapy

Martínez-Limón

Joaquin

Caballero

et al. 2020

IJMS

272

199

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“…But how CARD9 in tumor cells regulated p38 had not been elucidated yet. Based on great potential of p38-targeted therapy in liver cancer treatment [24,25], downregulated-CARD9-induced p38 activation was an important implication for clinical application of p38-targeted therapy in NSCLCs.…”

Section: E C T O R C a R D 9 S H C O N T R O L S H C A R Dmentioning

confidence: 99%

Caspase Recruitment Domain Containing Protein 9 Suppresses Non-Small Cell Lung Cancer Proliferation and Invasion via Inhibiting MAPK/p38 Pathway

et al. 2020

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PurposeCaspase recruitment domain containing protein 9 (CARD9) has been demonstrated to be a pro-tumor factor in various cancers. However, our previous study found a significant decrease of CARD9 in malignant pleural effusion compared with benign pleural effusion. So we investigated the role of CARD9 in non-small cell lung cancer (NSCLC) and its working mechanism. Materials and MethodsImmunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were used to detect the expression of CARD9 in specimens of NSCLC patients. The Cancer Genome Atlas (TCGA) databasewas also used to analyze the expression of CARD9 in NSCLC and its predicting value for prognosis. Immunofluorescence was used for CARD9 cellular location. Cell growth assay, clonal formation assay, wound healing assay, matrigel invasion assay, and flow cytometry were used to test cell proliferation, migration, invasion, apoptosis, and cycle progression of NSCLC cells with CARD9 knockdown or CARD9 overexpression. Co-immunoprecipitation was used to identify the interaction between CARD9 and B-cell lymphoma 10 (BCL10). SB203580 was used to inhibit p38 activation.ResultsCARD9 was decreased in NSCLC tissues compared with normal tissues; low CARD9 expression was associated with poor survival. CARD9 was expressed both in tumor cells and macrophages. Downregulation of CARD9 in NSCLC cells enhanced the abilities of proliferation, invasion and migration via activated MAPK/p38 signaling, while overexpression of CARD9 presented antitumor effects. BCL10 was identified to interact with CARD9.ConclusionWe demonstrate that CARD9 is an independent prognostic factor in NSCLC patients and inhibits proliferation, migration, and invasion by suppressing MAPK/p38 pathway in NSCLC cells.

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“…Indeed, p38 was shown to participate in the induction of pathologies such as inflammation-related diseases [19], autoimmune diseases [20], some types of cancer [6], and other pathologies, as specified later in this review. Interestingly, unlike other MAPKs, p38 demonstrates distinct and even opposing effects in different cancers, as it was shown to serve either as a tumor suppressor [21] or tumor promoter [22]. It was also shown that in some cases, it can perform both activities in different stages of cancer development [23].…”

Section: Introductionmentioning

confidence: 99%

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Maik-Rachline

Lifshits

Seger

2020

IJMS

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The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

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p38γ is essential for cell cycle progression and liver tumorigenesis

Cited by 82 publications

References 28 publications

The p38 Pathway: From Biology to Cancer Therapy

The p38 Pathway: From Biology to Cancer Therapy

Caspase Recruitment Domain Containing Protein 9 Suppresses Non-Small Cell Lung Cancer Proliferation and Invasion via Inhibiting MAPK/p38 Pathway

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

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