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 CRISPR/Cas9 treatment causes extended TP53-dependent cell cycle arrest in human cells

2020 ◽  
Vol 48 (16) ◽  
pp. 9067-9081
Author(s):  
Jonathan M Geisinger ◽  
Tim Stearns
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Target Sequence ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Dependent Cell ◽  
A Cell

Abstract While the mechanism of CRISPR/Cas9 cleavage is understood, the basis for the large variation in mutant recovery for a given target sequence between cell lines is much less clear. We hypothesized that this variation may be due to differences in how the DNA damage response affects cell cycle progression. We used incorporation of EdU as a marker of cell cycle progression to analyze the response of several human cell lines to CRISPR/Cas9 treatment with a single guide directed to a unique locus. Cell lines with functionally wild-type TP53 exhibited higher levels of cell cycle arrest compared to lines without. Chemical inhibition of TP53 protein combined with TP53 and RB1 transcript silencing alleviated induced arrest in TP53+/+ cells. Using dCas9, we determined this arrest is driven in part by Cas9 binding to DNA. Additionally, wild-type Cas9 induced fewer 53BP1 foci in TP53+/+ cells compared to TP53−/− cells and DD-Cas9, suggesting that differences in break sensing are responsible for cell cycle arrest variation. We conclude that CRISPR/Cas9 treatment induces a cell cycle arrest dependent on functional TP53 as well as Cas9 DNA binding and cleavage. Our findings suggest that transient inhibition of TP53 may increase genome editing recovery in primary and TP53+/+ cell lines.

scholarly journals CRISPR/Cas9 Treatment Causes Extended TP53-Dependent Cell Cycle Arrest In Human Cells

2019 ◽  
Author(s):  
Jonathan M. Geisinger ◽  
Tim Stearns
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Target Sequence ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Dependent Cell ◽  
A Cell

ABSTRACTWhile the mechanism of CRISPR/Cas9 cleavage is understood, the large variation in mutant recovery for a given target sequence between cell lines is much less clear. We hypothesized that this variation may be due to differences in how the DNA damage response affects cell cycle progression. We used incorporation of EdU as a marker of cell cycle progression to analyze the response of several human cell lines to CRISPR/Cas9 treatment with a single guide directed to a unique locus. Cell lines with functionally wild-type TP53 exhibited higher levels of cell cycle arrest compared to lines without. Chemical inhibition of TP53 protein combined with TP53 and RB1 transcript silencing alleviated induced arrest in TP53+/+ cells. This arrest is driven in part by Cas9 binding to DNA. Additionally, wild-type Cas9 induced fewer 53BP1 foci in TP53+/+ cells compared to TP53−/− cells, suggesting that differences in break sensing are responsible for cell cycle arrest variation. We conclude that CRISPR/Cas9 treatment induces a cell cycle arrest dependent on functional TP53 as well as Cas9 DNA binding and cleavage. Our findings suggest that transient inhibition of TP53 may increase genome editing efficiency in primary and TP53+/+ cell lines.

The Capacity of the Hypomethylating Agents Azacytidine and Decitabine to Induce Apoptosis and Cell Cycle Arrest Depends on the Activation of the DNA-Damage Response Pathway.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1655-1655
Author(s):  
Simone Boehrer ◽  
Lionel Ades ◽  
Nicolas Tajeddine ◽  
Lorenzo Galluzzi ◽  
Stephane de Botton ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Hypomethylating Agents ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Damage Response

Abstract Background: The hypomethylating agents azacytidine (AZA) and decitabine (DEC) have shown clinical efficacy in patients (pts) with MDS. There is in vitro evidence that both agents, in addition to their hypomethylating effect, also function by inducing apoptosis, cell cycle arrest and/or the activation of a DNA damage response (DDR). However, the exact contributions of those mechanisms of action and their functional interdependence remain to be defined. Methods: A panel of MDS (P39, MDS-1)- and AML (HL-60, KG-1)-derived cell lines were incubated with increasing dosages of AZA (1–2μM) and DEC (1–2μM) and the drugs capacity to induce apoptosis (DiOC6(3)/PI), cell cycle arrest (PI) and/or a DDR (immunoflourescence staining of P-ATM, P-Chk-1, P-Chk-2, γ-H2AX) were assessed in absence and presence of the ATM-inhibitor KU-55933 and the Chk-1 inhibitor UCN-01. Results: We show that both drugs induced dose-dependent apoptosis in myeloid cell lines: whereas AZA increased apoptosis in KG-1 and HL-60 by about 10% (48h, 2μM) the respective incubation with DEC augmented apoptosis by about 20% (HL-60) to 30% (KG-1). P39 cells were resistant to AZA and increased apoptosis by 15% after 48h of 2μM DEC, and MDS-1 cells were resistant to both drugs. In addition, both drugs induced a G2/M-arrest in P39 (+15% after 48h with 2μM of AZA or DEC) and HL-60 (+20% after 48h with 2μM of AZA or DEC) cells, but not in KG-1 and MDS-1 cells. Noteworthy, both drugs induced a DDR in the apoptosis-sensitive KG-1 cells (but not P39 cells) as evidenced by the appearance of nuclear P-ATM and γ-H2AX foci. Surprisingly, this activation of P-ATM did not induce the nuclear translocation of P-Chk-1-Ser317 or P-Chk-2-Ser68. To more clearly define the importance of the DDR in AZA- and DEC-induced apoptosis and G2/M-arrest, experiments were recapitulated in the presence of the ATM-inhibitor KU-55933 and the Chk-1 inhibitor UCN-01. Inhibition of ATM abrogated the apoptosis-inducing activity of AZA and DEC in KG-1 cells (without influencing cell cycle progression), whereas inhibition of Chk-1 remained without effect. In contrast, in P39 and HL-60 cells, inhibition of ATM neither affected cell cycle progression, nor sensitivity towards the drugs. Nevertheless, inhibition of Chk-1 by UCN-01 completely abrogated the G2/M-arresting effect of AZA (and diminished that of DEC) in P39 and HL-60 cells. Conclusions: We provide novel evidence for the cell-type dependent capacity of the hypomethylating agents 5-azacytidine and decitabine to induce apoptosis, cell-cycle arrest and DDR in cell lines representing different subtypes of MDS and AML. Moreover, we show the crucial role of ATM and Chk-1 activation – as part of the DDR – in mediating AZA and DEC apoptosis-inducing and cell cycle-arresting effects, respectively, providing evidence that hypomethylating agents confer their beneficial effects by employing different pathways of the DDR.

The HGF/c-Met Signaling Pathway in Hodgkin Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1551-1551
Author(s):  
Chuanhui Xu ◽  
Anke Van Den Berg ◽  
Arjan Diepstra ◽  
Miao Wang ◽  
Debora Jong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Hodgkin Lymphoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
M Cell ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Abstract 1551 Poster Board I-574 Introduction Hodgkin lymphoma (HL) is a B-cell neoplasm characterized by a minority of neoplastic cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, which are located within an extensive infiltrate of reactive cells. Aberrant signaling of various receptor tyrosine kinases (RTKs) via autocrine or paracrine mechanisms contributes to the survival and proliferation of HRS cells. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway has been implicated in the pathophysiology of many cancers, but its role in HL is poorly investigated. In this study, we investigated the expression of c-Met and HGF in HL patient tissues and studied the cell physiological effects of the HGF/c-Met signaling pathway using a c-Met tyrosine kinase inhibitor SU11274 in HL cell lines. Methods The expression of c-Met and HGF in HL patient tissues was studied by immunohistochemistry on a HL tissue microarray. The c-Met expression level was determined by Western blotting, while HGF mRNA and protein levels were measured by quantitative (q)RT-PCR and ELISA in four HL cell lines, i.e. L428, KMH2, L1236 and U-HO1. The effects of SU11274 treatment on the activity of the HGF/c-Met signaling pathway was determined by detection of phosphorylated downstream targets by Western blotting. Effects on cell growth and cell cycle were determined by 3-(4,5- Dimethylthiazol -2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and by flow cytometry with Propidium iodide (PI), respectively. Results C-Met was detected in HRS cells in 55% (26/47) of HL patient tissues. Expression of HGF was detected in HRS cells in 5 c-Met positive and 2 c-Met negative HL patient tissues. C-Met was highly expressed in L428 compared to three other HL cell lines, whereas HGF was highly expressed in KMH2 and not or only weakly in the other three HL cell lines. Detectable levels of phosphorylated c-Met (p-Met) were observed only in L428 consistent with the high basal expression level of c-Met. Phosphorylation of c-Met, Akt and Erk1/2 were upregulated upon HGF stimulation of L428 cells. This activation could be blocked by inhibiting c-Met activation with SU11274. In functional studies, SU11274 suppressed cell growth in L428, promoted G2/M cell cycle arrest after 24h incubation, and induced tetraploidy after 48h. Washing of the cells after induction of G2/M arrest resulted in normal cell cycle progression indicating that the G2/M cell cycle arrest was reversible. Inhibition of PI3K, MEK1/2 and Erk1/2, three downstream targets of the HGF/c-Met signaling pathway, also induced G2/M cell cycle arrest in L428, indicating that these factors are involved in the G2/M cell cycle arrest induced by SU11274. Conclusion Co-expression of c-Met and HGF in HRS cells was observed in 11% of the HL patient tissues and HGF/c-Met signaling pathway regulates cell growth and cell cycle progression in L428 cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

2002 ◽  
Vol 22 (12) ◽  
pp. 4309-4318 ◽  
Author(s):  
Latha Shivakumar ◽  
John Minna ◽  
Toshiyuki Sakamaki ◽  
Richard Pestell ◽  
Michael A. White
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest

ABSTRACT The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53

2021 ◽  
Vol 118 (44) ◽  
pp. e2102420118
Author(s):  
Alyssa M. Klein ◽  
Lynn Biderman ◽  
David Tong ◽  
Bita Alaghebandan ◽  
Sakina A. Plumber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Family Members ◽  
Wild Type ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Double Minute ◽  
Murine Double Minute ◽  
Wild Type P53

The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2–Murine Double Minute X (MDM2–MDMX) heterodimer. The role of MDM2–MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.

scholarly journals Hyperbaric oxygen promotes not only glioblastoma proliferation but also chemosensitization by inhibiting HIF1α/HIF2α-Sox2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Pan Wang ◽  
Sheng Gong ◽  
Jinyu Pan ◽  
Junwei Wang ◽  
Dewei Zou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Hyperbaric Oxygen ◽  
Cell Cycle Progression ◽  
Malignant Progression ◽  
Cycle Progression ◽  
Chemotherapy Sensitivity ◽  
Hypoxic Conditions ◽  
Cycle Arrest

AbstractThere exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.

scholarly journals Influenza A Virus Replication Induces Cell Cycle Arrest in G0/G1 Phase

2010 ◽  
Vol 84 (24) ◽  
pp. 12832-12840 ◽  
Author(s):  
Yuan He ◽  
Ke Xu ◽  
Bjoern Keiner ◽  
Jianfang Zhou ◽  
Volker Czudai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cell Cycle Progression ◽  
Virus Production ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Infected Cells

ABSTRACT Many viruses interact with the host cell division cycle to favor their own growth. In this study, we examined the ability of influenza A virus to manipulate cell cycle progression. Our results show that influenza A virus A/WSN/33 (H1N1) replication results in G0/G1-phase accumulation of infected cells and that this accumulation is caused by the prevention of cell cycle entry from G0/G1 phase into S phase. Consistent with the G0/G1-phase accumulation, the amount of hyperphosphorylated retinoblastoma protein, a necessary active form for cell cycle progression through late G1 into S phase, decreased after infection with A/WSN/33 (H1N1) virus. In addition, other key molecules in the regulation of the cell cycle, such as p21, cyclin E, and cyclin D1, were also changed and showed a pattern of G0/G1-phase cell cycle arrest. It is interesting that increased viral protein expression and progeny virus production in cells synchronized in the G0/G1 phase were observed compared to those in either unsynchronized cells or cells synchronized in the G2/M phase. G0/G1-phase cell cycle arrest is likely a common strategy, since the effect was also observed in other strains, such as H3N2, H9N2, PR8 H1N1, and pandemic swine H1N1 viruses. These findings, in all, suggest that influenza A virus may provide favorable conditions for viral protein accumulation and virus production by inducing a G0/G1-phase cell cycle arrest in infected cells.

scholarly journals Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

scholarly journals Human Papillomavirus Type 16 E7 Maintains Elevated Levels of the cdc25A Tyrosine Phosphatase during Deregulation of Cell Cycle Arrest

2002 ◽  
Vol 76 (2) ◽  
pp. 619-632 ◽  
Author(s):  
Don X. Nguyen ◽  
Thomas F. Westbrook ◽  
Dennis J. McCance
Keyword(s):  
Cell Cycle ◽  
Human Papillomavirus ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Tyrosine Phosphatase ◽  
Early Gene ◽  
Cycle Progression ◽  
Hpv 16 ◽  
Human Papillomavirus Type 16 ◽  
Cycle Arrest

ABSTRACT Essential to the oncogenic properties of human papillomavirus type 16 (HPV-16) are the activities encoded by the early gene product E7. HPV-16 E7 (E7.16) binds to cellular factors involved in cell cycle regulation and differentiation. These include the retinoblastoma tumor suppressor protein (Rb) and histone deacetylase (HDAC) complexes. While the biological significance of these interactions remains unclear, E7 is believed to help maintain cells in a proliferative state, thus establishing an environment that is conducive to viral replication. Most pathways that govern cell growth converge on downstream effectors. Among these is the cdc25A tyrosine phosphatase. cdc25A is required for G1/S transition, and its deregulation is associated with carcinogenesis. Considering the importance of cdc25A in cell cycle progression, it represents a relevant target for viral oncoproteins. Accordingly, the present study focuses on the putative deregulation of cdc25A by E7.16. Our results indicate that E7.16 can impede growth arrest induced during serum starvation and keratinocyte differentiation. Importantly, these E7-specific phenotypes correlate with elevated cdc25A steady-state levels. Reporter assays performed with NIH 3T3 cell lines and human keratinocytes indicate that E7 can transactivate the cdc25A promoter. In addition, transcriptional activation by E7.16 requires the distal E2F site within the cdc25A promoter. We further demonstrate that the ability of E7 to abrogate cell cycle arrest, activate cdc25A transcription, and increase cdc25A protein levels requires intact Rb and HDAC-1 binding domains. Finally, by using the cdk inhibitor roscovitine, we reveal that E7 activates the cdc25A promoter independently of cell cycle progression and cdk activity. Consequently, we propose that E7.16 can directly target cdc25A transcription and maintains cdc25A gene expression by disrupting Rb/E2F/HDAC-1 repressor complexes.

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