Ifitm3 (CD225) Mediates CD19-Dependent Survival and Proliferation During Normal B Cell Development and In Ph+ ALL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2505-2505 ◽  
Author(s):  
Jaewoong Lee ◽  
Huimin Geng ◽  
Zhengshan Chen ◽  
Eugene Park ◽  
Lars Klemm ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Surface Expression ◽  
Significant Inhibition ◽  
High Expression ◽  
Wild Type ◽  
Expression Levels ◽  
Cycle Arrest

Abstract Background IFITM (Interferon-induced transmembrane protein) also known as CD225 was identified as a gene that are transcriptionally induced downstream of interferon (IFN) signaling. Ifitm3, basally expressed on the plasma membrane, is associated with CD19 (B cell receptor components), CD81 and CD21 in mouse B cell. However, the specific roles of Ifitm3 in B cells remain unclear. Results We found that high expression levels of Ifitm1 and 3 mRNA in ALL patient samples at the time of diagnosis correlated with positive minimal residual disease (MRD) status in two clinical trials for patients with high risk acute lymphoblastic leukemia (n=207; COG P9906; p=0.005 and ECOG E2993; n=215; p=0.01). In addition, high expression levels of Ifitm3 mRNA at diagnosis predicts poor overall survival (OS) in Ph+ ALL patients (ECOG E2993; n=83; p=0.01). To study the function of Ifitm in Ph+ ALL, B cell progenitors from Ifitm3-/- mice lacking Ifitm3 were transformed with BCR-ABL1. Loss of Ifitm3 showed significant cell cycle arrest in the G0/G1 phase (42.5%, p<0.001) compared to wild-type Ph+ ALL cells (28%) through increased levels of p53, p21. Interestingly, loss of Ifitm3 also showed upregulation of AKTS473 phosphorylation and c-Myc expression, well-established markers of oncogene-induced senescence with accumulation of p53. β-galactosidase assay revealed that loss of Ifitm3 induced 2.8 fold (P=0.04) higher cellular senescence than wild-type Ph+ ALL cells. Moreover, treatment of Adriamycin (25 ng ml-1) for induction of low level of DNA damage significantly induced cellular senescence on most Ifitm3-/- Ph+ ALL cells, but had no effect on wild-type Ph+ ALL cells. Consistent with Ifitm3-mediated proliferative defects of Ph+ ALL cells, Ifitm3-/- Ph+ ALL cells exhibited reduced self-renewal capacity with 0.33 fold (P=0.0004) decreased colony in colony forming assay compared to wild-type Ph+ ALL cells. Furthermore, Ifitm3 deficient B cell progenitors also showed significant inhibition of proliferation with inhibition of phosphorylation of Stat5Y694 and c-Myc expression. We found that loss of Ifitm3 leads to impaired membrane expression of CD19 in both B cell progenitors and Ph+ ALL cells. 4-hydroxytamoxifen (4-OHT)-inducible activation of CD19 enhanced the proliferation of wild-type Ph+ ALL cells and completely rescued proliferative defects in Ifitm3 deficient B cell progenitors with release from G0/G1 cell cycle arrest associated with upregulation of phosphorylation of Stat5 Y694 and c-Myc expression. Phosphorylation of BTKY223 known as downstream effector of CD19 was also induced by forced expression of CD19 in both wild-type and Ifitm3 deficient B cell progenitors. In addition, we found that CD19 positively regulates the surface expression of IL7R in B cell progenitors. Interestingly, CD19low population in Ifitm3 deficient B cell progenitors showed lower surface expression of IL7R compared to CD19high population. In contrast to B cell progenitors, forced expression of CD19 did not increase the proliferation of wild-type Ph+ ALL cells. Surprisingly, upregulation of CD19 induced apoptosis in Ifitm3-deficient Ph+ ALL cells with significant inhibition of BCR-ABL1 activity, phosphorylation of Stat5Y694, BTKY223and Bcl2 expression. Conclusions These findings identify novel role of Ifitm3 in both B cell progenitors and Ph+ ALL cells. Ifitm3 regulates the dual function of CD19 as a positive regulator of IL7R, which mediates the proliferation of B cell progenitors and as a negative regulator, limiting the activity of BCR-ABL1 in Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

The Tumor Suppressor PTEN Is Required to Prevent Cellular Senescence and Cell Cycle Arrest In B Cell Lineage and Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 513-513
Author(s):  
Seyedmehdi Shojaee ◽  
Consuelo Garcia ◽  
Hong Wu ◽  
Markus Muschen
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Myeloid Leukemia ◽  
Cell Lineage ◽  
Leukemia Cells ◽  
Cycle Arrest ◽  
Pten Deletion

Abstract Abstract 513 Background: The phosphatase and tensin homolog (PTEN) tumor suppressor is a negative regulator of PI3K/AKT signaling and frequently deleted in solid tumors and in T cell lineage acute lymphoblastic leukemia (ALL). Recent work by our group demonstrated that Pten-deletion cooperates with WNT/β-catenin signaling in self-renewal signaling of leukemia stem cells in T cell lineage ALL (Guo et al., Nature 2008). Although PTEN deletions are uncommon in B cell lineage ALL and chronic myeloid leukemia, recent work identified Pten as a tumor suppressor in B cell lineage ALL and chronic myeloid leukemia (CML; Peng et al., Blood 2010). This study showed that Pten-deletion accelerated leukemia in B cell lineage ALL and CML and increased self-renewal capacity of leukemia stem cells. Approach: To investigate the mechanism of Pten-mediated negative regulation of leukemia proliferation and stem cell self-renewal in B cell lineage ALL and CML, we established a conditional mouse model for inducible ablation of Pten in BCR-ABL1-driven B cell lineage ALL and CML. To this end, B cell precursors or Lin− Sca-1+ c-Kit+ (LSK) cells from the bone marrow of Pten-fl/fl mice were transduced with retroviral BCR-ABL1 under B lymphoid or myeloid conditions. When growth-factor-independent B cell lineage or CML-like leukemia formed, Pten-fl/fl leukemia cells were transduced with tamoxifen (4-OHT)-inducible Cre-ERT2 or an ERT2 empty vector control. Results: Deletion of Pten was induced by 4-OHT treatment and near-complete deletion of Pten was observed on day 2 after Cre-ERT2 induction as determined by genomic PCR and Western blot. As expected, deletion of Pten resulted in a strong increase of phospho-AKT, as determined by Western blot. Surprisingly, deletion of Pten in B cell lineage leukemia and CML-like disease did not accelerate leukemia cell growth and had the opposite effect. After three days of Cre-induction, the vast majority of both B cell lineage and CML-like leukemia cells underwent cellular senescence, as measured by staining for senescence-associated β-galactosidase activity (>100-fold increase; p=0.0008). In addition, Pten-deletion induced cell cycle arrest in both G0/G1 and G2/M phase of the cell cycle, which is consistent with cellular senescence. While growth kinetics and viability of Pten-fl/fl leukemia cells carrying the ERT2 empty vector control remained unchanged, Pten-deletion caused a reduction of viability by 80% within 6 days. Compared to B cell lineage leukemia and CML-like leukemia, Pten protein levels were very low in normal B cell precursors and myeloid progenitor cells and the consequences of Pten-deletion were less drastic in normal as compared to leukemia cells. Consistent with cellular senescence, deletion of Pten resulted in dramatic upregulation of p53 and p21 but not p27 cell cycle inhibitors. We recently identified BCL6 as a FoxO-dependent suppressor of p53 in BCR-ABL1-driven leukemias (Duy et al., J Exp Med 2010). Since Pten functions as a positive regulator of FoxO1, FoxO3A and FoxO4, we tested whether excessive upregulation of p53 and cellular senescence were a consequence of loss of BCL6/FoxO function downstream of Pten-deletion. Treatment of BCR-ABL1 B cell lineage and CML-like leukemia cells with Imatinib results in strong upregulation of BCL6 expression downstream of FoxO factors. Upon deletion of Pten, however, Imatinib-treatment failed to upregulate BCL6. In the absence of Pten, BCL6 protein expression was undetectable and p53 protein levels were excessively increased. Conclusion: Pten has been extensively studied as a tumor suppressor in a broad range of malignancies. It is frequently deleted in solid tumors and also in T cell lineage ALL, where Pten-deletion accelerates leukemia cell growth by increased PI3K/AKT survival signaling. In B cell lineage and CML-like leukemia, Pten deletion also increases PI3K/AKT signaling. Unlike T-ALL, however, B cell lineage leukemia and CML cells undergo cellular senescence and cell cycle arrest. In B cell lineage ALL and CML, the BCL6 transcriptional repressor is required to overcome p53-dependent senescence. Here we unexpectedly identify the PTEN phosphatase as a central requirement for FoxO-dependent upregulation of BCL6. Hence, PTEN signaling via FoxO/BCL6 is required for the ability of the BCR-ABL1 ALL and CML cells to evade p53-mediated cellular senescence. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IFITM3 (CD225) Regulates CD19 Surface Expression and CD19-Mediated Activation of PI3K Signaling in Pre-B Acute Lymphoblastic Leukemia Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1070-1070
Author(s):  
Jae-Woong Lee ◽  
Huimin Geng ◽  
Zhengshan Chen ◽  
Eugene Park ◽  
Angela Park ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Surface Expression ◽  
Akt Signaling ◽  
Significant Inhibition ◽  
Mrna Levels ◽  
Wild Type ◽  
Cycle Arrest ◽  
Cd19 Expression

Abstract Background & Hypothesis: IFITM3 (Interferon-induced transmembrane protein 3) also known as CD225/Leu-13 was identified as interferon-inducible molecule in the context of viral infection. IFITM3 encodes a surface receptor, basally expressed on the plasma membrane, that is associated with known B cell co-receptors including CD19, CD81 and CD21 on mouse and human B cells. However, besides its interaction with CD19, specific functions of Ifitm3 in normal B cells development and, potentially leukemogenesis, are not known. Recent approaches based on CD19-specific chimeric antigen receptors (CAR) have achieved spectacular successes in eliminating pre-B ALL cells based on surface expression of CD19 (e.g. Grupp et al., N Engl J Med 2013). However, in some cases, CD19 CAR treatment was followed by ALL relapse developing from a clone that lacked CD19 surface expression. Therefore, we studied factors that can potentially regulate CD19 surface on normal and leukemic pre-B cells. Results: Studying IFITM3 mRNA levels in ALL cells at the time of diagnosis in clinical trials for childhood (COG P9906) and adult ALL (ECOG E2993), we found that higher than median expression levels of IFITM3 predicted shorter overall and relapse-free survival (P=0.014). In addition, patients with higher than median IFITM3 mRNA levels at the time of diagnosis were significantly more likely to experience ALL relapse and had a higher risk of a positive MRD status at the end of induction chemotherapy. To study the function of Ifitm3 in a model for human pre-B ALL, pre-B cells from Ifitm3-/- mice were transformed with BCR-ABL1. Strikingly, deletion of IFITM3 resulted in near-complete loss of CD19 expression on the surface of normal and leukemic pre-B cells. Besides loss of surface expression, loss of Ifitm3 also caused impaired phosphorylation of CD19-Y513, which mediates downstream activation of PI3K-AKT signaling in both B cell progenitors and pre-B ALL cells. Reconstitution of IFITM3 in patient-derived pre-B ALL cells rescued both CD19 expression and increased phosphorylation of CD19-Y513 together with downstream SRC, SYK, PI3K signaling. Co-immunoprecipitation experiments revealed that the cytoplasmic tail of IFITM3 interacts with CD19, LYN, SYK, PI3K p110δ and AKT, pointing to a central role of IFITM3 in regulating CD19/PI3K-AKT signaling in pre-B cells and pre-B ALL. Deletion of Ifitm3 also resulted in significant cell cycle arrest in the G0/G1 phase (P<0.001) and increased protein levels of p53 and p21 compared to wild-type pre-B ALL cells. Moreover, treatment with low dose adriamycin (25 ng ml-1) for induction of modest DNA damage significantly induced cellular senescence in Ifitm3-/- but not wild-type pre-B ALL cells. Consistent with Ifitm3-mediated proliferative defects of Ph+ ALL cells, Ifitm3-/- Ph+ ALL cells exhibited reduced self-renewal capacity (P=0.0004) decreased colony in colony forming assay compared to wild-type cells. Furthermore, Ifitm3 deficient B cell progenitors also showed significant inhibition of proliferation with inhibition of phosphorylation of Stat5Y694and c-Myc expression. 4-hydroxytamoxifen (4-OHT)-inducible activation of CD19 rescued proliferative defects in Ifitm3 deficient B cell progenitors with release from G0/G1 cell cycle arrest associated with upregulation of phosphorylation of Stat5 Y694 and c-Myc expression. In addition, we found that CD19 positively regulates the surface expression of IL7R in B cell progenitors. Interestingly, CD19low population in Ifitm3 deficient B cell progenitors showed lower surface expression of IL7R compared to CD19high population. In contrast to B cell progenitors, forced expression of CD19 did not increase the proliferation of wild-type Ph+ ALL cells. Surprisingly, upregulation of CD19 induced apoptosis in Ifitm3-deficient Ph+ ALL cells with significant inhibition of BCR-ABL1 activity, phosphorylation of Stat5Y694and Bcl2 expression. Conclusion: These findings identify novel role of IFITM3 in regulating CD19 surface expression and CD19-Y513 mediated PI3K-AKT signaling in pre-B cells and pre-B ALL. Preliminary experiment showed that agonistic antibodies against IFITM3/CD225 increased CD19/PI3K-AKT signaling and proliferation in pre-B ALL cells and future studies will elucidate whether blocking antibodies (e.g. decoy Fc-fusion molecules) will have useful effects in targeting CD19/PI3K-AKT signaling in human pre-B ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1453
Author(s):  
Haoran Wang ◽  
Jianhua Wei ◽  
Hong Jiang ◽  
Ye Zhang ◽  
Caina Jiang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Antitumor Agents ◽  
Mechanistic Study ◽  
Ros Generation ◽  
Polypyridyl Complexes ◽  
Expression Levels ◽  
Cycle Arrest ◽  
Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

scholarly journals Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 302 ◽  
Author(s):  
Xin Zhang ◽  
Yao Qin ◽  
Zhaohai Pan ◽  
Minjing Li ◽  
Xiaona Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
G1 Phase ◽  
Therapeutic Effects ◽  
Human Gastric Cancer ◽  
Expression Levels ◽  
Cycle Arrest

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

scholarly journals Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e42150 ◽  
Author(s):  
Sascha Schäuble ◽  
Karolin Klement ◽  
Shiva Marthandan ◽  
Sandra Münch ◽  
Ines Heiland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Quantitative Model ◽  
Cycle Arrest

scholarly journals Dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest

Genomics ◽  
2020 ◽  
Vol 112 (2) ◽  
pp. 1309-1317 ◽  
Author(s):  
Zhen Zhao ◽  
Qiongye Dong ◽  
Xuehui Liu ◽  
Lei Wei ◽  
Liyang Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Transcriptome Profiling ◽  
Cycle Arrest

scholarly journals Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Larissa Kido ◽  
Eun-Ryeong Hahm ◽  
Valeria Cagnon ◽  
Mário Maróstica ◽  
Shivendra Singh
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cell Cycle Distribution ◽  
Mutant P53 ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

scholarly journals Oncogenic ras and p53 Cooperate To Induce Cellular Senescence

2002 ◽  
Vol 22 (10) ◽  
pp. 3497-3508 ◽  
Author(s):  
Gerardo Ferbeyre ◽  
Elisa de Stanchina ◽  
Athena W. Lin ◽  
Emmanuelle Querido ◽  
Mila E. McCurrach ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Map Kinase ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Null Mouse ◽  
P53 Expression ◽  
Oncogenic Ras ◽  
Cycle Arrest ◽  
Murine Fibroblasts ◽  
Mitogen Activated Protein

ABSTRACT Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53val135 ) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19ARF was required for this effect, since p53 −/− ARF −/− double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19ARF on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53 −/− mdm2 −/− double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our 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.

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