scholarly journals An autoregulatory cell cycle timer integrates growth and specification in chick wing digit development

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Joseph Pickering ◽  
Kavitha Chinnaiya ◽  
Matthew Towers
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Sonic Hedgehog ◽  
Fundamental Question ◽  
Cyclin D2 ◽  
A Cell ◽  
Wing Bud ◽  
Underlying Mechanisms ◽  
Digit Identity ◽  
Little Finger

A fundamental question is how proliferation and growth are timed during embryogenesis. Although it has been suggested that the cell cycle could be a timer, the underlying mechanisms remain elusive. Here we describe a cell cycle timer that operates in Sonic hedgehog (Shh)-expressing polarising region cells of the chick wing bud. Our data are consistent with Shh signalling stimulating polarising region cell proliferation via Cyclin D2, and then inhibiting proliferation via a Bmp2-p27kip1 pathway. When Shh signalling is blocked, polarising region cells over-proliferate and form an additional digit, which can be prevented by applying Bmp2 or by inhibiting D cyclin activity. In addition, Bmp2 also restores posterior digit identity in the absence of Shh signalling, thus indicating that it specifies antero-posterior (thumb to little finger) positional values. Our results reveal how an autoregulatory cell cycle timer integrates growth and specification and are widely applicable to many tissues.

scholarly journals Follicle-Stimulating Hormone Inhibits Adenosine 5′-Monophosphate-Activated Protein Kinase Activation and Promotes Cell Proliferation of Primary Granulosa Cells in Culture through an Akt-Dependent Pathway

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 929-935 ◽  
Author(s):  
Pradeep P. Kayampilly ◽  
K. M. J. Menon
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Protein Kinase ◽  
Mrna Expression ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Ampk Activation ◽  
Cyclin D2 ◽  
Cell Cycle Inhibitor ◽  
Dependent Pathway

FSH, acting through multiple signaling pathways, regulates the proliferation and growth of granulosa cells, which are critical for ovulation. The present study investigated whether AMP-activated protein kinase (AMPK), which controls the energy balance of the cell, plays a role in FSH-mediated increase in granulosa cell proliferation. Cells isolated from immature rat ovaries were grown in serum-free, phenol red free DMEM-F12 and were treated with FSH (50 ng/ml) for 0, 5, and 15 min. Western blot analysis showed a significant reduction in AMPK activation as observed by a reduction of phosphorylation at thr 172 in response to FSH treatment at all time points tested. FSH also reduced AMPK phosphorylation in a dose-dependent manner with maximum inhibition at 100 ng/ml. The chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, 0.5 mm) increased the cell cycle inhibitor p27 kip expression significantly, whereas the AMPK inhibitor (compound C, 20 μm) and FSH reduced p27kip expression significantly compared with control. FSH treatment resulted in an increase in the phosphorylation of AMPK at ser 485/491 and a reduction in thr 172 phosphorylation. Inhibition of Akt phosphorylation using Akt inhibitor VIII reversed the inhibitory effect of FSH on thr 172 phosphorylation of AMPK, whereas ERK inhibitor U0126 had no effect. These results show that FSH, through an Akt-dependent pathway, phosphorylates AMPK at ser 481/495 and inhibits its activation by reducing thr 172 phosphorylation. AMPK activation by 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment resulted in a reduction of cell cycle regulatory protein cyclin D2 mRNA expression, whereas FSH increased the expression by 2-fold. These results suggest that FSH promotes granulosa cell proliferation by increasing cyclin D2 mRNA expression and by reducing p27 kip expression by inhibiting AMPK activation through an Akt-dependent pathway. FSH stimulates granulosa cell proliferation by reducing cell cycle inhibitor p27 kip through AMP kinase inhibition.

scholarly journals Circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

2020 ◽  
Author(s):  
Xinhua Qu ◽  
Liumei Zhu ◽  
Linlin Song ◽  
Shaohua Liu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Regulatory Network ◽  
Inhibitory Effect ◽  
Cervical Carcinogenesis ◽  
Activation Assay ◽  
Cell Cycle Related Gene ◽  
Rna Immunoprecipitation ◽  
A Cell ◽  
Brdu Assay

Abstract Background: Cervical cancer (CC) is a highly malignant tumor. Evolving researches on CC have unveiled a concept that circRNA exerts important roles in CC progression. In this study, we mainly explored the role of a novel circRNA, circ_0084927, and its regulatory network in the development of CC.Methods: qRT-PCR was applied to evaluate the expression of circ_0084927, miR-1179 and CDK2 mRNA in CC tissues and cells. Dual-luciferase reporting experiments and RNA immunoprecipitation (RIP) assay were conducted to validate the target relationship of miR-1179 with circ_0084927 and CDK2 mRNA. CCK-8 and BrdU assay was used to evaluate CC cell proliferation. The adhesion and apoptosis phenotypes of CC cells were measured by cell-matrix adhesion and caspase 3 activation assay. Flow cytometry was employed to detect CC cell cycle.Results: Our results indicated that circ_0084927 was up-regulated in CC tissues and cells, and circ_0084927 silence inhibited CC cell proliferation and adhesion, while facilitating apoptosis as well as triggering cell cycle arrest. On the other hand, miR-1179 down-regulation appeared in CC tissues. Additionally, circ_0084927 abolished miR-1179’s inhibitory effects on cell proliferation and adhesion. Our study showed that CDK2 was up-regulated in CC tissues and played a cancer-promoting role. Furthermore, miR-1179 directly targeted CDK2, thereby inhibiting CDK2’s promotion on the malignant phenotypes of CC cells. circ_0084927 revoked the inhibitory effect of miR-1179 on CDK2 by sponging miR-1179.Conclusion: Circ_0084927 promoted cervical carcinogenesis by sequestering miR-1179 that directly targeted CDK2. Our results shed light on the circ_0084927/miR-1179/CDK2 regulatory network that strengthened CC aggressiveness, providing novel candidate targets for CC treatment.

scholarly journals The effects of 5α-dihydrotestosterone on the kinetics of cell proliferation in rat prostate

1974 ◽  
Vol 142 (3) ◽  
pp. 483-489 ◽  
Author(s):  
Barry Lesser ◽  
Nicholas Bruchovsky
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cellular Growth ◽  
Velocity Sedimentation ◽  
Growth Fraction ◽  
Subcutaneous Injections ◽  
Daughter Cells ◽  
A Cell ◽  
Rat Prostate ◽  
Kinetics Of

The regenerating rat prostate was used as an experimental model to determine the effects of 5α-dihydrotestosterone on certain parameters of cell proliferation, including the duration of the phases of the cell cycle and the size of the cellular growth fraction. Rats castrated 7 days previously were treated with daily subcutaneous injections of 5α-dihydrotestosterone for 14 days; 48h after the beginning of therapy, cells in the process of DNA synthesis were labelled with a single injection of radioactive thymidine and the progress of these cells through the division cycle was observed. Cell-cycle analysis was performed by fractionating prostatic nuclei according to their position in the cell cycle by using the technique of velocity sedimentation under unit gravity. The results indicate that during regeneration the cell population undergoes 1.8 doublings with a doubling time of 40h, and that the process involves almost four rounds of cell division with a cell-generation time of 20h. The growth fraction at any time is about 0.5, and about half the daughter cells produced do not re-enter the proliferative cycle. All cells present at the start of regeneration eventually undergo at least one division during the course of regeneration, although any given cell can divide from one to four times.

c-Jun N-terminal kinase/c-Jun inhibits fibroblast proliferation by negatively regulating the levels of stathmin/oncoprotein 18

2010 ◽  
Vol 430 (2) ◽  
pp. 345-354 ◽  
Author(s):  
Yvonne Y. C. Yeap ◽  
Ivan H. W. Ng ◽  
Bahareh Badrian ◽  
Tuong-Vi Nguyen ◽  
Yan Y. Yip ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Cell System ◽  
Tumour Suppressor Protein ◽  
Oncoprotein 18 ◽  
A Cell ◽  
Cancer Types ◽  
Type C ◽  
Interfering Rna

The JNKs (c-Jun N-terminal kinases) are stress-activated serine/threonine kinases that can regulate both cell death and cell proliferation. We have developed a cell system to control JNK re-expression at physiological levels in JNK1/2-null MEFs (murine embryonic fibroblasts). JNK re-expression restored basal and stress-activated phosphorylation of the c-Jun transcription factor and attenuated cellular proliferation with increased cells in G1/S-phase of the cell cycle. To explore JNK actions to regulate cell proliferation, we evaluated a role for the cytosolic protein, STMN (stathmin)/Op18 (oncoprotein 18). STMN, up-regulated in a range of cancer types, plays a crucial role in the control of cell division through its regulation of microtubule dynamics of the mitotic spindle. In JNK1/2-null or c-Jun-null MEFs or cells treated with c-Jun siRNA (small interfering RNA), STMN levels were significantly increased. Furthermore, a requirement for JNK/cJun signalling was demonstrated by expression of wild-type c-Jun, but not a phosphorylation-defective c-Jun mutant, being sufficient to down-regulate STMN. Critically, shRNA (small hairpin RNA)-directed STMN down-regulation in JNK1/2-null MEFs attenuated proliferation. Thus JNK/c-Jun regulation of STMN levels provides a novel pathway in regulation of cell proliferation with important implications for understanding the actions of JNK as a physiological regulator of the cell cycle and tumour suppressor protein.

scholarly journals Human Speedy

2002 ◽  
Vol 157 (3) ◽  
pp. 357-366 ◽  
Author(s):  
Lisa A. Porter ◽  
Ryan W. Dellinger ◽  
John A. Tynan ◽  
Elizabeth A. Barnes ◽  
Monica Kong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
S Phase ◽  
Cell Cycle Gene ◽  
Cell Cycle Protein ◽  
Cell Progression ◽  
A Cell ◽  
Immortalized Cell ◽  
Cycle Regulation

The decision for a cell to self-replicate requires passage from G1 to S phase of the cell cycle and initiation of another round of DNA replication. This commitment is a critical one that is tightly regulated by many parallel pathways. Significantly, these pathways converge to result in activation of the cyclin-dependent kinase, cdk2. It is, therefore, important to understand all the mechanisms regulating cdk2 to determine the molecular basis of cell progression. Here we report the identification and characterization of a novel cell cycle gene, designated Speedy (Spy1). Spy1 is 40% homologous to the Xenopus cell cycle gene, X-Spy1. Similar to its Xenopus counterpart, human Speedy is able to induce oocyte maturation, suggesting similar biological characteristics. Spy1 mRNA is expressed in several human tissues and immortalized cell lines and is only expressed during the G1/S phase of the cell cycle. Overexpression of Spy1 protein demonstrates that Spy1 is nuclear and results in enhanced cell proliferation. In addition, flow cytometry profiles of these cells demonstrate a reduction in G1 population. Changes in cell cycle regulation can be attributed to the ability of Spy1 to bind to and prematurely activate cdk2 independent of cyclin binding. We demonstrate that Spy1-enhanced cell proliferation is dependent on cdk2 activation. Furthermore, abrogation of Spy1 expression, through the use of siRNA, demonstrates that Spy1 is an essential component of cell proliferation pathways. Hence, human Speedy is a novel cell cycle protein capable of promoting cell proliferation through the premature activation of cdk2 at the G1/S phase transition.

scholarly journals Coupling of proadipocyte growth arrest and differentiation. II. A cell cycle model for the physiological control of cell proliferation.

1982 ◽  
Vol 94 (2) ◽  
pp. 400-405 ◽  
Author(s):  
R E Scott ◽  
B J Hoerl ◽  
J J Wille ◽  
D L Florine ◽  
B R Krawisz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Growth Arrest ◽  
Biological Processes ◽  
Cycle Model ◽  
Physiological Control ◽  
Physiological Factors ◽  
Regulatory Processes ◽  
A Cell

Experimental evidence is presented that supports a cell cycle model showing that there are five distinct biological processes involved in proadipocyte differentiation. These include: (a) growth arrest at a distinct state in the G1 phase of the cell cycle; (b) nonterminal differentiation; (c) terminal differentiation; (d) loss of the differentiated phenotype; and (e) reinitiation of cell proliferation. Each of these events is shown to be regulated by specific human plasma components or other physiological factors. At two states designated GD and GD', coupling of growth arrest and differentiation is shown to occur. We propose that these mechanisms for the coupling of growth arrest and differentiation are physiologically significant and mimic the regulatory processes that control stem cell proliferation in vivo.

scholarly journals Circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

2020 ◽  
Author(s):  
Xinhua Qu ◽  
Liumei Zhu ◽  
Linlin Song ◽  
Shaohua Liu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Regulatory Network ◽  
Inhibitory Effect ◽  
Cervical Carcinogenesis ◽  
Activation Assay ◽  
Cell Cycle Related Gene ◽  
Rna Immunoprecipitation ◽  
A Cell ◽  
Brdu Assay

Abstract Background: Cervical cancer (CC) is a highly malignant tumor. Evolving researches on CC have unveiled a concept that circRNA exerts important roles in CC progression. In this study, we mainly explored the role of a novel circRNA, circ_0084927, and its regulatory network in the development of CC. Methods: qRT-PCR was applied to evaluate the expression of circ_0084927, miR-1179 and CDK2 mRNA in CC tissues and cells. Dual-luciferase reporting experiments and RNA immunoprecipitation (RIP) assay were conducted to validate the target relationship of miR-1179 with circ_0084927 and CDK2 mRNA. CCK-8 and BrdU assay was used to evaluate CC cell proliferation. The adhesion and apoptosis phenotypes of CC cells were measured by cell-matrix adhesion and caspase 3 activation assay. Flow cytometry was employed to detect CC cell cycle. Results: Our results indicated that circ_0084927 was up-regulated in CC tissues and cells, and circ_0084927 silence inhibited CC cell proliferation and adhesion, while facilitating apoptosis as well as triggering cell cycle arrest. On the other hand, miR-1179 down-regulation appeared in CC tissues. Additionally, circ_0084927 abolished miR-1179’s inhibitory effects on cell proliferation and adhesion. Our study showed that CDK2 was up-regulated in CC tissues and played a cancer-promoting role. Furthermore, miR-1179 directly targeted CDK2, thereby inhibiting CDK2’s promotion on the malignant phenotypes of CC cells. circ_0084927 revoked the inhibitory effect of miR-1179 on CDK2 by sponging miR-1179. Conclusion: Circ_0084927 promoted cervical carcinogenesis by sequestering miR-1179 that directly targeted CDK2. Our results shed light on the circ_0084927/miR-1179/CDK2 regulatory network that strengthened CC aggressiveness, providing novel candidate targets for CC treatment.

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