scholarly journals TGFβ and PTHrP Control Chondrocyte Proliferation by Activating Cyclin D1 Expression

2001 ◽  
Vol 12 (12) ◽  
pp. 3852-3863 ◽  
Author(s):  
Frank Beier ◽  
Zenobia Ali ◽  
Dereck Mok ◽  
Allison C. Taylor ◽  
Todd Leask ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Bone Development ◽  
Chondrocyte Proliferation ◽  
Endochondral Bone ◽  
Cycle Progression ◽  
Related Transcription Factor

Exact coordination of growth plate chondrocyte proliferation is necessary for normal endochondral bone development and growth. Here we show that PTHrP and TGFβ control chondrocyte cell cycle progression and proliferation by stimulating signaling pathways that activate transcription from the cyclin D1 promoter. The TGFβ pathway activates the transcription factor ATF-2, whereas PTHrP uses the related transcription factor CREB, to stimulate cyclin D1 promoter activity via the CRE promoter element. Inhibition of cyclin D1 expression with antisense oligonucleotides causes a delay in progression of chondrocytes through the G1 phase of the cell cycle, reduced E2F activity, and decreased proliferation. Growth plates from cyclin D1–deficient mice display a smaller zone of proliferating chondrocytes, confirming the requirement for cyclin D1 in chondrocyte proliferation in vivo. These data identify the cyclin D1 gene as an essential component of chondrocyte proliferation as well as a fundamental target gene of TGFβ and PTHrP during skeletal growth.

scholarly journals Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function

2001 ◽  
Vol 21 (3) ◽  
pp. 794-810 ◽  
Author(s):  
James S. Foster ◽  
Donald C. Henley ◽  
Antonin Bukovsky ◽  
Prem Seth ◽  
Jay Wimalasena
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Inhibitory Activity ◽  
Cell Cycle Progression ◽  
Estrogen Action ◽  
Cycle Progression ◽  
Cdk2 Activity ◽  
Mcf 7

ABSTRACT Estrogens induce proliferation of estrogen receptor (ER)-positive MCF-7 breast cancer cells by stimulating G1/S transition associated with increased cyclin D1 expression, activation of cyclin-dependent kinases (Cdks), and phosphorylation of the retinoblastoma protein (pRb). We have utilized blockade of cyclin D1-Cdk4 complex formation through adenovirus-mediated expression of p16INK4a to demonstrate that estrogen regulates Cdk inhibitor expression and expression of the Cdk-activating phosphatase Cdc25A independent of cyclin D1-Cdk4 function and cell cycle progression. Expression of p16INK4a inhibited G1/S transition induced in MCF-7 cells by 17-β-estradiol (E2) with associated inhibition of both Cdk4- and Cdk2-associated kinase activities. Inhibition of Cdk2 activity was associated with delayed removal of Cdk-inhibitory activity in early G1 and decreased cyclin A expression. Cdk-inhibitory activity and expression of both p21Cip1 and p27Kip1 was decreased, however, in both control and p16INK4a-expressing cells 20 h after estrogen treatment. Expression of Cdc25A mRNA and protein was induced by E2 in control and p16INK4a-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16INK4a. Inhibition of Cdc25A activity in p16INK4a-expressing cells was associated with depressed Cdk2 activity and was reversed in vivo and in vitro by active Cdk2. Transfection of MCF-7 cells with a dominant-negative Cdk2 construct inhibited the E2-dependent activation of ectopic Cdc25A. Supporting a role for Cdc25A in estrogen action, antisenseCDC25A oligonucleotides inhibited estrogen-induced Cdk2 activation and DNA synthesis. In addition, inactive cyclin E-Cdk2 complexes from p16INK4a-expressing, estrogen-treated cells were activated in vitro by treatment with recombinant Cdc25A and in vivo in cells overexpressing Cdc25A. The results demonstrate that functional association of cyclin D1-Cdk4 complexes is required for Cdk2 activation in MCF-7 cells and that Cdk2 activity is, in turn, required for the in vivo activation of Cdc25A. These studies establish Cdc25A as a growth-promoting target of estrogen action and further indicate that estrogens independently regulate multiple components of the cell cycle machinery, including expression of p21Cip1 and p27Kip1.

scholarly journals A negative reciprocal regulatory axis between cyclin D1 and HNF4α modulates cell cycle progression and metabolism in the liver

2020 ◽  
Vol 117 (29) ◽  
pp. 17177-17186 ◽  
Author(s):  
Heng Wu ◽  
Yitzhak Reizel ◽  
Yue J. Wang ◽  
Jessica L. Lapiro ◽  
Betsy T. Kren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Glycogen Synthesis ◽  
Hepatocyte Proliferation ◽  
In Vivo Model ◽  
Large Network ◽  
Cell Cycle Protein ◽  
Cycle Progression

Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver.

scholarly journals Blocking the transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibits apoptosis and induces tumor growth in SCID mice.

1996 ◽  
Vol 183 (3) ◽  
pp. 1205-1213 ◽  
Author(s):  
R C Bargou ◽  
C Wagener ◽  
K Bommert ◽  
W Arnold ◽  
P T Daniel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Dominant Negative ◽  
Serum Starvation ◽  
Cycle Progression ◽  
Transcription Factor E2f

The transcription factor E2F is regulated during the cell cycle through interactions with the product of the retinoblastoma susceptibility gene and related proteins. It is thought that E2F-mediated gene regulation at the G1/S boundary and during S phase may be one of the rate-limiting steps in cell proliferation. It was reported that in vivo overexpression of E2F-1 in fibroblasts induces S phase entry and leads to apoptosis. This observation suggests that E2F plays a role in both cell cycle regulation and apoptosis. To further understand the role of E2F in cell cycle progression, cell death, and tumor development, we have blocked endogenous E2F activity in HBL-100 cells, derived from nonmalignant human breast epithelium, using dominant-negative mutants under the control of a tetracycline-dependent expression system. We have shown here that induction of dominant-negative mutants led to strong downregulation of transiently transfected E2F-dependent chloramphenicol acetyl transferase reporter constructs and of endogenous c-myc, which has been described as a target gene of the transcription factor E2F/DP. In addition, we have shown that blocking of E2F could efficiently protect from apoptosis induced by serum starvation within a period of 10 d, whereas control cells started to die after 24 h. Surprisingly, blocking of E2F did not alter the rate of proliferation or of DNA synthesis of these cells; this finding indicates that cell-cycle progression could be driven in an E2F-independent manner. In addition, we have been able to show that blocking of endogenous E2F in HBL-100 cells led to rapid induction of tumor growth in severe combined immunodeficiency mice. No tumor growth could be observed in mice that received mock-transfected clones or tetracycline to block expression of the E2F mutant constructs in vivo. Thus, it appears that E2F has a potential tumor-suppressive function under certain circumstances. Furthermore, we provide evidence that dysregulation of apoptosis may be an important step in tumorigenesis.

scholarly journals Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo

Cell Cycle ◽  
2009 ◽  
Vol 8 (17) ◽  
pp. 2802-2809 ◽  
Author(s):  
Eric A. Hanse ◽  
Christopher J. Nelsen ◽  
Melissa M. Goggin ◽  
Chelsea K. Anttila ◽  
Lisa K. Mullany ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Cycle Progression

scholarly journals Differential effects of 16α-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells

2005 ◽  
Vol 34 (1) ◽  
pp. 91-105 ◽  
Author(s):  
Joan S Lewis ◽  
T J Thomas ◽  
Richard G Pestell ◽  
Chris Albanese ◽  
Michael A Gallo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
D1 Protein ◽  
Fold Increase ◽  
Cycle Progression ◽  
Cyclin D1 Protein ◽  
Mcf 7

We studied the effects of 2-methoxyestradiol (2-ME2) and 16α-hydroxyestrone (16α-OHE1), two metabolites of estradiol (E2), on DNA synthesis, cell cycle progression and cyclin D1 protein levels in estrogen receptor-positive MCF-7 cells. E2 and 16α-OHE1 stimulated DNA synthesis, and 2-ME2 inhibited the stimulatory effects of these agents. E2 and 16α-OHE1 stimulated the progression of cells from G1 to S phase and this effect was attenuated by 2-ME2. Western blot analysis showed that E2 and 16α-OHE1 increased cyclin D1 protein level by about fourfold compared with control. 2-ME2 had no significant effect on cyclin D1; however, it prevented the accumulation of cyclin D1 in the presence of E2 and 16α-OHE1. Cells transfected with a cyclin D1 reporter gene and treated with E2 or 16α-OHE1 showed 7- and 9.5-fold increase respectively in promoter activity compared with control. This activity was significantly inhibited by 2-ME2. Cyclin D1 transactivation was mediated by the cAMP response element (CRE) region, which binds activating transcription factor 2 (ATF-2). DNA affinity assay showed 2.5- and 3.5-fold increases in ATF-2 binding to CRE in the presence of E2 and 16α-OHE1 respectively. The binding of ATF-2 was inhibited by the presence of 2-ME2. These results show that 2-ME2 can downregulate cyclin D1 and thereby cell cycle progression by a mechanism involving the disruption of ATF-2 binding to cyclin D1 promoter.

scholarly journals Circular RNA-DPP4 serves an oncogenic role in prostate cancer progression through regulating miR-195/cyclin D1 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Deping Yang ◽  
Bo Yang ◽  
Yanjun Zhu ◽  
Qianlin Xia ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cyclin D1 ◽  
Microarray Analysis ◽  
Cell Cycle Progression ◽  
Normal Prostate ◽  
Cycle Progression

Abstract Background Recently, more and more studies have highlighted the critical regulatory roles of circular RNAs (circRNAs), a class of non-coding RNAs, in the progression of many human cancers, including prostate cancer (PCa). circRNA microarray analysis was performed to identify circRNAs that are differentially expressed in PCa tissues. Methods 104 pairs of PCa tissues and matched adjacent normal prostate tissues (at least 2 cm distal to the tumor margin) were obtained. circRNA microarray analysis was performed on four pairs of PCa tissues and matched adjacent normal prostate tissues to investigate the potential involvement of circRNAs in PCa. Flow cytometric analysis was performed to investigate whether the effect of circDPP4 on PCa cell proliferation was associated with the alteration in cell cycle progression. The role of circDPP4 in PCa tumor growth was further explored in vivo. Results We found that circDPP4 was overexpressed in PCa tissues and cell lines, and its expression was closely associated with Gleason score and clinical stage of PCa patients. In vitro loss- and gain-of-function experiments demonstrated that circDPP4 knockdown inhibited, whereas circDPP4 overexpression promoted the proliferation, migration, invasion and cell cycle progression of PCa cells. Knockdown of circDPP4 also suppressed PCa tumor growth in vivo. We further found that circDPP4 functioned as a competing endogenous RNA (ceRNA) for miR-195 in PCa cells, and miR-195 negatively regulated the expression of oncogenic cyclin D1. Rescue experiments suggested that restoration of miR-195 blocked the oncogenic role of circDPP4 in PCa cells. Conclusions Taken together, our findings revealed a novel regulatory mechanism between circDPP4 and miR-195/cyclin D1 axis, and offered novel strategies for the treatment of PCa.

Transcription factors important for starting the cell cycle in yeast

1993 ◽  
Vol 340 (1293) ◽  
pp. 351-360 ◽  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Dna Replication ◽  
Transcriptional Activation ◽  
Feedback Loop ◽  
Cell Cycle Progression ◽  
Regulatory Subunit ◽  
Cycle Progression ◽  
Embryonic Cleavage ◽  
Related Transcription Factor

Unlike early embryonic cleavage divisions in certain animals, cell-cycle progression in yeast and probably also in all metazoan somatic cells requires the periodic transcriptional activation of certain key genes. Thus far, the only clear examples are genes that encode a class of unstable ‘cyclin’ proteins, which bind and activate the cdc2/Cdc28 protein kinase: the G1-specific cyclins encoded by CLN1 and CLN2 , a B-type cyclin implicated in DNA replication encoded by CLB5 ; and four B-type cyclins involved in mitosis encoded by CLB1, 2, 3, 4. CLN1, CLN2 , and CLB5 are transcribed in late G1, as cells undergo Start. A transcription factor composed of Swi4 and Swi6 proteins (called SBF) activates CLN1 and CLN2 transcription via a positive feedback loop in which Cln proteins activate their own transcription. A different but related transcription factor called MBF seems responsible for the late G1-specific transcription of most DNA replication genes including CLB5 . We have purified MBF and shown that it contains Swi6 and a 110-120 kDa protein distinct from Swi4 (pl20) that contacts DNA. Thus, we propose that SBF and MBF share a common regulatory subunit (Swi6) but recognize their promoter elements via distinct DNA binding subunits.

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