Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin

Han, Zhiyong; Wei, Wenyi; Dunaway, Stephen; Darnowski, James W.; Calabresi, Paul; Sedivy, John M.; Hendrickson, Eric A.; Balan, Kannan V.; Pantazis, Panayotis; Wyche, James H.

doi:10.1074/jbc.m112401200

Cited by 221 publications

(157 citation statements)

References 71 publications

(56 reference statements)

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…As reported earlier (Han et al, 2002;Rodriguez and Meuth, 2006), control siRNA transfected cells showed an accumulation of G2-phase cells 48 h after the CPT treatment (Figure 6b). In comparison, CHK1-ablated cells showed less G2 phase accumulation and instead, a higher sub-G1 content (Figure 6b and c).…”

Section: Fem1b As a Novel Chk1 Mediator T-p Sun And S-y Shiehsupporting

confidence: 86%

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

View full text Add to dashboard Cite

Human checkpoint kinase 1 (CHK1) is an essential kinase required to preserve genome stability, and is activated by DNA replication blockage through the ataxia-telangiectasia-mutated-and-Rad3-related (ATR)/ATRIP-signaling pathway. In this report, we show that a novel CHK1-interacting protein, FEM1B (human homologue of the Caenorhabditis elegans sex determination fem1 protein), identified by a yeast two-hybrid screen, is involved in the activation of CHK1 by replication stress. Depletion of FEM1B by small interfering RNA in cancer cells impairs the activation of CHK1 kinase activity and attenuates the induction of CHK1 Ser345 phosphorylation upon replication interference. It is to be noted that, CHK2 Thr68 phosphorylation is not altered by FEM1B downregulation. By fractionation, we further demonstrated that FEM1B is able to associate with chromatin, and such association facilitates chromatin loading of the Rad9 protein. Consistently, ATR activity is poorly maintained in FEM1B knockdown cells; and FEM1B-ablated cells are as sensitive to replication block as CHK1-depleted cells. Our study has uncovered an adaptor protein FEM1B, which acts as a bridge linking CHK1 and Rad9, thus facilitating checkpoint signaling induced by replication stress.

show abstract

Section: Fem1b As a Novel Chk1 Mediator T-p Sun And S-y Shiehsupporting

confidence: 86%

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Shieh

2009

Oncogene

View full text Add to dashboard Cite

show abstract

“…When halogenated nucleoside derivative 5-chloro-2 0 -deoxyuridine was used instead of BrdU, it synergized with DMA and activated STAT1 similar to BrdU (Supplementary Figure 1h). Other genotoxic compounds known to induce DNA replication stress and senescence in cancer cells, such as APH, HU ( (Yogev et al, 2006), Supplementary Figures 1i-l), thymidine and camptothecin ( (Han et al, 2002;Engstrom and Kmiec, 2007), data not shown) also activated and induced STAT1. APH or HU used individually at concentrations inducing an obvious senescent phenotype in HeLa cells induced phosphorylation of STAT1 at both sites and induction of total STAT1 to levels ( Figure 1e) higher than that induced by BrdU or DMA alone, but not to the level induced by combined BrdU þ DMA.…”

Section: Resultsmentioning

confidence: 96%

“…Chronic subtoxic doses of stress-inducing compounds such as ethanol or H 2 O 2 can cause stress-induced senescence (Toussaint et al, 2002). Drug-induced senescence can be promoted by a variety of chemically and functionally unrelated DNA-damaging anticancer agents, such as doxorubicin (Chang et al, 1999), camptothecin (Han et al, 2002), 5-aza-2 0 -deoxycytidine (Timmermann et al, 1998;Kulaeva et al, 2003), aphidicolin (APH) and hydroxyurea (HU) (Yogev et al, 2006), or halogenated nucleotide analogs such as 5-bromo-2 0 -deoxyuridine (BrdU) (Michishita et al, 1999;Minagawa et al, 2005). Despite the fact that oncogenic or stress stimuli do not promote telomere shortening, prematurely senescent cells share similar characteristics with cells undergoing replicative senescence.…”

Section: Introductionmentioning

confidence: 99%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

View full text Add to dashboard Cite

Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2 0 -deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon c (IFNc), IFNb and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/ chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNb-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

show abstract

“…30 PIR mRNA levels showed a fivefold decrease after 24 hours of CPT treatment, and a decrease in protein expression was clearly detectable after 48 hours ( Figure 6D). Increased size, flattened morphology, and positive staining for SA-␤-galactosidase activity after 96 hours of CPT treatment confirmed that cells had undergone senescence ( Figure 6E).…”

Section: Pir Expression Is Down-regulated By Braf Activation and Campmentioning

confidence: 96%

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Licciulli

Luise

Scafetta

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression.

show abstract

Role of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin

Cited by 221 publications

References 71 publications

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress

Cytokine expression and signaling in drug-induced cellular senescence

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Contact Info

Product

Resources

About