scholarly journals Control of multiciliogenesis by miR-34/449 in the male reproductive tract through enforcing cell cycle exit

2021 ◽  
Author(s):  
Yu-Jie Wu ◽  
Yue Liu ◽  
Yan-Qin Hu ◽  
Li Wang ◽  
Fu-Rong Bai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Reproductive Tract ◽  
Surface Defects ◽  
Kinase Inhibitor ◽  
Cell Cycle Control ◽  
Apical Surface ◽  
Cell Cycle Exit ◽  
Double Knockout ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cilia Formation

Multiciliated cells (MCCs) are terminally differentiated, post-mitotic cells that possess hundreds of motile cilia on their apical surface. Defects in cilia formation are associated with ciliopathies that affect many organs. In the present study, we tested the role and mechanism of the miR-34/449 family in the regulation of multiciliogenesis in efferent ductules (EDs) using a miR-34b/c−/-; miR-449−/- double knockout (dKO) mouse model. MiR-34b/c and miR-449 depletion led to a reduced number of MCCs and abnormal cilia structure in the EDs starting from postnatal day 14. However, abnormal MCC differentiation in the dKO EDs could be observed as early as postnatal day 7. RNA-seq analyses revealed that the aberrant development of MCCs in the EDs of dKO mice was associated with upregulation of genes involved in cell cycle control. Using a cyclin dependent kinase inhibitor to force cell cycle exit promoted MCC differentiation, and partially rescued the defective multiciliogenesis in the EDs of dKO mice. Taken together, our results suggested that miR-34b/c and miR-449 play an essential role in multiciliogenesis in EDs by regulating cell cycle exit.

scholarly journals Deceleration of cell cycle underpins a switch from proliferative- to terminal division in plant stomatal lineage

2021 ◽  
Author(s):  
Soon-Ki Han ◽  
Jiyuan Yang ◽  
Machiko Arakawa ◽  
Rie Iwasaki ◽  
Tomoaki Sakamoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Cell Cycle Control ◽  
Control Plant ◽  
Time Lapse ◽  
Cell Types ◽  
Symmetric Division ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Asymmetric Divisions ◽  
Stomatal Lineage

Differentiation of specialized cell types from self-renewing progenitors requires precise cell cycle control. Plant stomata are generated through asymmetric divisions of a stem-cell-like precursor meristemoid followed by the single symmetric division that creates an adjustable pore surrounded by paired guard cells. The stomatal-lineage-specific transcription factor MUTE terminates the asymmetric divisions and triggers differentiation. However, the role of cell cycle machinery in this transition remains unknown. Through time-lapse imaging, we discover that the symmetric division is slower than the asymmetric division. We identify a plant-specific cyclin-dependent kinase inhibitor, SIAMESE-RELATED4 (SMR4), as a molecular brake that decelerates cell cycle during this transition. SMR4 is directly induced by MUTE and transiently accumulates in differentiating meristemoids. SMR4 physically and functionally associates with CYCD3;1 and extends G1-phase of asymmetric divisions. By contrast, SMR4 fails to interact with CYCD5;1, a MUTE-induced G1 cyclin, and permits the symmetric division. Our work unravels a molecular framework of the proliferation-to-differentiation switch within the stomatal lineage and suggests that a timely proliferative cell cycle is critical for the stomatal fate specification.

Human lactoferrin controls the level of retinoblastoma protein and its activityThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function, and Applications, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (3) ◽  
pp. 345-350 ◽  
Author(s):  
Hee-Joung Son ◽  
Shin-Hee Lee ◽  
Sang-Yun Choi
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Kinase Inhibitor ◽  
Peer Review Process ◽  
Cell Cycle Control ◽  
Retinoblastoma Protein ◽  
Cyclin Dependent Kinase ◽  
Antiproliferative Effects ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Selection Of

Lactoferrin (Lf) has been implicated in the regulation of cell growth. However, the molecular mechanism underlying this effect remains to be elucidated. In this study, we show that Lf is involved in the cell cycle control system in a variety of cell lines, through retinoblastoma protein (Rb) - mediated growth arrest. We observed that Lf induces the expression of Rb, a signal mediator of cell cycle control, and that a majority of this Lf-induced Rb persists in a hypophosphorylated form. In addition, we determined that Lf specifically augments the level of a cyclin-dependent kinase inhibitor, p21, but not p27. Upon treatment with Lf, H1299 cells expressing defective p53 effected an augmentation of endogenous p21 levels, which may contribute to the accumulation of hypophosphorylated Rb. A substantial quantity of active Rb binds more efficiently to E2F1 in cells that express Lf and consequently blocks the expression of an E2F1-responsive gene, thereby suggesting that Lf plays a crucial role in the inhibition of tumor cell growth. Therefore, we conclude that the antiproliferative effects of Lf can likely be attributed to the elevated levels of hypophosphorylated Rb.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

p57(Kip2) regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina

Development ◽  
2000 ◽  
Vol 127 (16) ◽  
pp. 3593-3605 ◽  
Author(s):  
M.A. Dyer ◽  
C.L. Cepko
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Kinase Inhibitor ◽  
Retinal Development ◽  
Cell Types ◽  
Cell Cycle Exit ◽  
Retinal Progenitor Cells ◽  
Mouse Development ◽  
Retinal Progenitor ◽  
Cyclin Kinase Inhibitor

A precise balance between proliferation and differentiation must be maintained during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors can regulate cell cycle exit coincident with induction of differentiation programs during development. We have found that the p57(Kip2) cyclin kinase inhibitor is upregulated during G(1)/G(0) in a subset of retinal progenitor cells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse development. Retroviral mediated overexpression of p57(Kip2) in embryonic retinal progenitor cells led to premature cell cycle exit. Retinae from mice lacking p57(Kip2) exhibited inappropriate S-phase entry and apoptotic nuclei were found in the region where p57(Kip2) is normally expressed. Apoptosis precisely compensated for the inappropriate proliferation in the p57(Kip2)-deficient retinae to preserve the correct proportion of the major retinal cell types. Postnatally, p57(Kip2) was found to be expressed in a novel subpopulation of amacrine interneurons. At this stage, p57(Kip2)did not regulate proliferation. However, perhaps reflecting its role during this late stage of development, animals lacking p57(Kip2) showed an alteration in amacrine subpopulations. p57(Kip2) is the first gene to be implicated as a regulator of amacrine subtype/subpopulation development. Consequently, we propose that p57(Kip2) has two roles during retinal development, acting first as a cyclin kinase inhibitor in mitotic progenitor cells, and then playing a distinct role in neuronal differentiation.

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