p38α MAP Kinase as a Sensor of Reactive Oxygen Species in Tumorigenesis

Dolado, Ignacio; Swat, Aneta; Ajenjo, Nuria; Vita, Gabriella De; Cuadrado, Ana; Nebreda, Ángel R.

doi:10.1016/j.ccr.2006.12.013

Cited by 361 publications

(340 citation statements)

References 52 publications

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“…While ROS can induce DNA damage, Sun et al (2007) have also shown that ROS may trigger senescence via a kinase cascade involving p38 and one of its effector kinases known as PRAK, which can phosphorylate and activate p53. Despite these findings, not all oncogenes increase ROS (for example, Raf, myc; Ray et al, 2006;Dolado et al, 2007), and it is still unknown whether a single activated Ras allele is capable of inducing sufficiently high levels of ROS. Therefore, the relative involvement of ROS in triggering the senescence response might be dictated by the specific genetic event and the resulting signal intensity.…”

Section: Ros P38 and Prakmentioning

confidence: 99%

Many roads lead to oncogene-induced senescence

2008

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Section: Ros P38 and Prakmentioning

confidence: 99%

Many roads lead to oncogene-induced senescence

2008

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“…All ROS studies were basically preformed as previously described (Dolado et al, 2007). adNull-or flag-tagged adTCTP-infected MCF10A cells were incubated with 20 mM DPI, 1 mM MYX, 10 mM PP2 or 10 mM LY294002 for 1 h, washed with PBS and incubated with 10 mM CM-DCFH PBS supplemented with 5.5 mM glucose.…”

Section: Ros Generationmentioning

confidence: 99%

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

et al. 2011

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Translationally controlled tumor protein (TCTP) is implicated in cell growth and malignant transformation. TCTP has been found to interact directly with the third cytoplasmic domain of the a subunit of Na,K-ATPase, but whether this interaction has a role in tumorigenesis is unclear. In this study, we examined TCTP-induced tumor progression signaling networks in human breast epithelial cells, using adenoviral infection. We found that TCTP (a) induces Src release from Na,K-ATPase a subunit and Src activation; (b) phosphorylates tyrosine residues 845, 992, 1086, 1148 and 1173 on anti-epidermal growth factor receptor (EGFR); (c) activates PI3K (phosphatidylinositol 3-kinase )-AKT, Ras-Raf-MEK-ERK1/2, Rac-PAK1/ 2, MKK3/6-p38 and phospholipase C (PLC)-c pathways; (d) enhances NADPH oxidase-dependent reactive oxygen species (ROS) generation; (e) stimulates cytoskeletal remodeling and cell motility and (f) upregulates matrix metalloproteinase (MMP) 3 and 13. These findings suggest that TCTP induces tumorigenesis through distinct multicellular signaling pathways involving Src-dependent EGFR transactivation, ROS generation and MMP expression.

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“…p38a negatively regulates the malignant transformation induced by oncogenic Ras, even in the absence of functional p53 response (Dolado et al, 2007). Different mechanisms have been proposed to explain this tumor suppressive role, including the (M17) were grown in the presence of 10% FBS.…”

Section: Discussionmentioning

confidence: 99%

“…activation of p53-dependent cell cycle arrest (Bulavin et al, 2002), induction of premature senescence (Wang et al, 2002) and upregulation of cell cycle inhibitors, such as p16 and p21 (Bulavin and Fornace, 2004) (Nicke et al, 2005). However, p38a is not a general inhibitor of oncogenic transformation; it specifically modulates malignant transformations induced by oncogenes that produce ROS (Dolado et al, 2007). Notably, some human cancer cells can bypass the inhibitory role of p38a on ROS accumulation, and this leads to enhanced tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

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p38α limits the contribution of MAP17 to cancer progression in breast tumors

et al. 2012

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MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in proteinexpressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38a activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38a. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS.

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p38α MAP Kinase as a Sensor of Reactive Oxygen Species in Tumorigenesis

Cited by 361 publications

References 52 publications

Many roads lead to oncogene-induced senescence

Many roads lead to oncogene-induced senescence

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

p38α limits the contribution of MAP17 to cancer progression in breast tumors

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