p21WAF1 Control of Epithelial Cell Cycle and Cell Fate

2002 ◽  
Vol 13 (6) ◽  
pp. 453-464 ◽  
Author(s):  
Wendy C. Weinberg ◽  
Mitchell F. Denning
Keyword(s):  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Fate ◽  
Cell Biology ◽  
Kinase Inhibitor ◽  
Growth Arrest ◽  
Nuclear Antigen ◽  
Central Position ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor

As a broad-acting cyclin-dependent kinase inhibitor, p21WAF1 occupies a central position in the cell cycle regulation of self-renewing tissues such as oral mucosa and skin. In addition to regulating normal cell cycle progression decisions, p21WAF1 integrates genotoxic insults into growth arrest and apoptotic signaling pathways that ultimately determine cell fate. As a result of its complex interactions with cell cycle machinery and response to mutagenic agents, p21WAF1 also has stage-specific roles in epithelial carcinogenesis. Finally, a view is emerging of p21WAF1 as not merely a cyclin-dependent kinase inhibitor, but also as a direct participant in regulating genes involved in growth arrest, senescence, and aging, thus providing an additional layer of control over matters of the cell cycle. This review discusses these various roles played by p21WAF1 in cell cycle control, and attempts to relate these to epithelial cell biology, with special emphasis on keratinocytes. (Abbreviations used include the following: Brdu, 5-Bromo-2-deoxyuridine; cdk, cyclin-dependent kinase; EGF, epidermal growth factor; KIP, kinase inhibitor protein; PCNA, proliferating cell nuclear antigen; and TPA, 12-O-tetradecanoylphorbol-13-acetate.)

scholarly journals Epstein-Barr Virus Nuclear Antigen 3A Promotes Cellular Proliferation by Repression of the Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1

2014 ◽  
Vol 10 (10) ◽  
pp. e1004415 ◽  
Author(s):  
Melissa L. Tursiella ◽  
Emily R. Bowman ◽  
Keith C. Wanzeck ◽  
Robert E. Throm ◽  
Jason Liao ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Nuclear Antigen ◽  
Cyclin Dependent Kinase ◽  
Barr Virus ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Epstein Barr

scholarly journals A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

2018 ◽  
Vol 115 (10) ◽  
pp. 2532-2537 ◽  
Author(s):  
Frank S. Heldt ◽  
Alexis R. Barr ◽  
Sam Cooper ◽  
Chris Bakal ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Kinase Inhibitor ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Serum Stimulation ◽  
G1 Cells ◽  
External Stimuli

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.

345 GENE EXPRESSION IN OOCYTES AFTER MEIOTIC INHIBITION WITH THE CYCLIN-DEPENDENT KINASE INHIBITOR BUTYROLACTONE I

2010 ◽  
Vol 22 (1) ◽  
pp. 329
Author(s):  
C. L. V. Leal ◽  
S. Mamo ◽  
T. Fair ◽  
P. Lonergan
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Relative Abundance ◽  
Kinase Inhibitor ◽  
Expression Profiles ◽  
Cyclin Dependent Kinase ◽  
Oocyte Competence ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Bovine Oocytes

Once removed from the follicle, mammalian oocytes resume meiosis spontaneously and progress through breakdown of the germinal vesicle to the matured state at metaphase II. The ability to reversibly inhibit such meiotic resumption has been reported and is a potentially useful method for studying developmental competence acquisition in oocytes as well as in some cases allowing flexibility in an IVF system where oocytes are collected from distant locations or on different days. The aim of the present study was to determine the effect of temporary inhibition of meiotic resumption using the cyclin-dependent kinase inhibitor butyrolactone I (BLI) on gene expression in bovine oocytes. Immature bovine oocytes were recovered from the ovaries of slaughtered heifers at a commercial abattoir and assigned to 1 of 4 groups: (1) Control: immature oocytes were collected either immediately or (2) after IVM for 24 h in TCM-199 containing 10 ng mL-1 EGF and 10% (v/v) FCS, (3) Inhibited oocytes collected either 24 h after incubation in the presence of 100 μM BLI in TCM-199 with 3 mg mL-1 BSA or (4) after meiotic inhibition for 24 h followed by in vitro maturation. All cultures were carried out at 38.5°C under 5% CO2 in air and maximum humidity. For mRNA relative abundance analysis, cumulus cells were removed and pools of 10 denuded oocytes were snap frozen in liquid nitrogen and stored at -80°C until use. A total of 42 transcripts, previously reported to be related to cell cycle regulation and/or oocyte competence were evaluated by quantitative real time PCR. Differences in relative abundance were analyzed by ANOVA and Student’s t-test. The majority of transcripts were downregulated (P < 0.05) after IVM in control oocytes (23 out of 42) and the same pattern was observed in inhibited oocytes that were allowed to mature. Twelve transcripts remained stable (P > 0.05) after IVM in control oocytes; of these, only two (PTTG1 and INHBA) did not show the same pattern in inhibited and matured oocytes. Few genes (7) were upregulated after IVM in control oocytes (P < 0.05) and of these, three (PLAT1, RBP1, and INHBB) were not upregulated in inhibited oocytes after IVM. Inhibited oocytes showed similar levels of expression (P > 0.05) as immature control oocytes, except for two genes (LUM and INHBB), which were increased in these oocytes (P < 0.05). The expression profiles of cell cycle genes were mostly unaffected by the BLI treatment. The few genes affected were previously reported as competence-related and could be useful markers of oocyte competence following pretreatment. In conclusion, the changes occurring in transcript abundance during oocyte maturation in vitro were to a large extent mirrored following inhibition of meiotic resumption prior to IVM and subsequent release from inhibition and maturation. CLV Leal was supported by CNPq, Brazil (PDE 201487/2007-1); Supported by Science Foundation Ireland (07/SRC/B1156).

scholarly journals The CRL4Cdt2 Ubiquitin Ligase Mediates the Proteolysis of Cyclin-Dependent Kinase Inhibitor Xic1 through a Direct Association with PCNA

2010 ◽  
Vol 30 (17) ◽  
pp. 4120-4133 ◽  
Author(s):  
Dong Hyun Kim ◽  
Varija N. Budhavarapu ◽  
Carlos R. Herrera ◽  
Hyung Wook Nam ◽  
Yu Sam Kim ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Proliferating Cell Nuclear Antigen ◽  
Kinase Inhibitor ◽  
Binding Domain ◽  
Nuclear Antigen ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Terminal Domain ◽  
Lysine Residues ◽  
Proliferating Cell

ABSTRACT During DNA polymerase switching, the Xenopus laevis Cip/Kip-type cyclin-dependent kinase inhibitor Xic1 associates with trimeric proliferating cell nuclear antigen (PCNA) and is recruited to chromatin, where it is ubiquitinated and degraded. In this study, we show that the predominant E3 for Xic1 in the egg is the Cul4-DDB1-XCdt2 (Xenopus Cdt2) (CRL4Cdt2) ubiquitin ligase. The addition of full-length XCdt2 to the Xenopus extract promotes Xic1 turnover, while the N-terminal domain of XCdt2 (residues 1 to 400) cannot promote Xic1 turnover, despite its ability to bind both Xic1 and DDB1. Further analysis demonstrated that XCdt2 binds directly to PCNA through its C-terminal domain (residues 401 to 710), indicating that this interaction is important for promoting Xic1 turnover. We also identify the cis-acting sequences required for Xic1 binding to Cdt2. Xic1 binds to Cdt2 through two domains (residues 161 to 170 and 179 to 190) directly flanking the Xic1 PCNA binding domain (PIP box) but does not require PIP box sequences (residues 171 to 178). Similarly, human p21 binds to human Cdt2 through residues 156 to 161, adjacent to the p21 PIP box. In addition, we identify five lysine residues (K180, K182, K183, K188, and K193) immediately downstream of the Xic1 PIP box and within the second Cdt2 binding domain as critical sites for Xic1 ubiquitination. Our studies suggest a model in which both the CRL4Cdt2 E3- and PIP box-containing substrates, like Xic1, are recruited to chromatin through independent direct associations with PCNA.

scholarly journals Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3110 ◽  
Author(s):  
Sakiko Nishikawa ◽  
Yuka Itoh ◽  
Muneshige Tokugawa ◽  
Yasumichi Inoue ◽  
Ken-ichi Nakashima ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Fate ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Sophora Flavescens ◽  
Promoter Activation ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Stress Relieving ◽  
A Cell ◽  
Cellular Stresses

In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.

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