PRAK Is Essential for ras-Induced Senescence and Tumor Suppression

@article{Sun2007PRAKIE,
  title={PRAK Is Essential for ras-Induced Senescence and Tumor Suppression},
  author={Peiqing Sun and Naoto Yoshizuka and Liguo New and Bettina A Moser and Yi-lei Li and Rong Liao and Changchuan Xie and Jianming Chen and Qingdong Deng and Maria Yamout and Meng-qiu Dong and Costa Frangou and John R. Yates and Peter E. Wright and Jiahuai Han},
  journal={Cell},
  year={2007},
  volume={128},
  pages={295-308}
}

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References

SHOWING 1-10 OF 45 REFERENCES

Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling.

TLDR
The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Ras mitogenic signaling.

High Intensity ras Signaling Induces Premature Senescence by Activating p38 Pathway in Primary Human Fibroblasts*

TLDR
Moderate ras activity mediated transformation in cooperation with E6E7 and hTERT, suggesting that a moderate intensity ras signal can provide sufficient oncogenic activities for tumorigenesis and that the development of tumors with relatively low ras activities may not need to acquire genetic alterations that bypass premature senescence.

Oncogenic ras and p53 Cooperate To Induce Cellular Senescence

TLDR
Results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

TLDR
It is shown that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency, and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.

Senescence of human fibroblasts induced by oncogenic Raf.

TLDR
It is concluded that the kinase cascade initiated by Raf can regulate the expression of p16(Ink4a) and the proliferative arrest and senescence that follows and may provide a defense against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.

Oncogene-induced senescence as an initial barrier in lymphoma development

TLDR
H3K9me-mediated senescence is identified as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.

The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins.

TLDR
The critical role of p300 and CBP in the senescence response that limits the oncogenic potential of ras has provided a mechanistic basis for the tumor-suppressing function of these proteins.

Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence.

TLDR
Stable expression of an activated form of MKK6 (MKK6EE), a direct activator of the stress-induced p38(HOG) mitogen-activated protein kinase pathway is sufficient for inducing features of senescence including a flattened, vacuolated, and irregular morphology, staining for acidic beta-galactosidase, and accumulation of age-associated pigments.

Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence

TLDR
Oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells and has provided new insights into how ras confers oncogenic transformation in primary cells.