PRAK Is Essential for ras-Induced Senescence and Tumor Suppression

  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},

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PRAK Suppresses Oncogenic ras-Induced Hematopoietic Cancer Development by Antagonizing the JNK Pathway

It is shown that PRAK deletion accelerates hematopoietic cancer development in a mouse model harboring an oncogenic ras allele, Eμ-N-RasG12D, specifically expressed in hematopolietic cells, and that PraK may function as a tumor suppressor in multiple types of cancers.

Induction of p38δ Expression Plays an Essential Role in Oncogenic ras-Induced Senescence

These findings indicate that induction of the prosenescent function of p38δ by oncogenic ras is achieved through 2 mechanisms, transcriptional activation by the Raf-1–MEK–ERK–AP-1/Ets pathway, which increases the cellular concentration of the p38 δ protein, and posttranslational modification by MKK3/6, which stimulates the enzymatic activity of p 38δ.

p38α and p38γ Mediate Oncogenic ras-induced Senescence through Differential Mechanisms*

It is demonstrated that p38α and p38γ, but not p38β, play an essential role in oncogenic ras-induced senescence, providing insights into the molecular mechanisms underlying the differential involvement of the p38 isoforms insenescence induction.

A new p53 target gene, RKIP, is essential for DNA damage-induced cellular senescence and suppression of ERK activation.

Evaluated the effects of p53 on the extracellular signal-regulated kinase (ERK) activation and found that p53 could suppress ERK activation through de novo synthesis and suggested that RKIP is an essential protein for cellular senescence.

The pathways to tumor suppression via route p38.

A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induced senescence.

Induction of p38 (cid:1) Expression Plays an Essential Role in Oncogenic ras -Induced Senescence

These studies indicate that induction of the prosenescent function of p38 (cid:1) by oncogenic ras is achieved through 2 mechanisms, transcriptional activation by the Raf-1–MEK–ERK–AP-1/Ets pathway, and posttranslational modification by MKK3/6, which stimulates the enzymatic activity of p 38 ( cid: 1) .

Tumor suppression by p53: making cells senescent.

How p53 regulates senescence and future studies about p53 family members insenescence are discussed, including p63 and p73, two homologues of p53 that have similar function in cell cycle arrest and apoptosis.

RAS induced senescence of skin keratinocytes is mediated through Rho‐associated protein kinase (ROCK)

Y‐27632 treated cultured RAS‐keratinocytes formed tumors in the absence of the inhibitor when placed in skin orthografts suggesting that factors in the tumor microenvironment can overcome the drive to senescence imparted by overactive ROCK activity.



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

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*

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

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

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.

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

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.

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.

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

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.