scholarly journals Lgr5+ intestinal stem cells reside in an unlicensed G1 phase

2018 ◽  
Vol 217 (5) ◽  
pp. 1667-1685 ◽  
Author(s):  
Thomas D. Carroll ◽  
Ian P. Newton ◽  
Yu Chen ◽  
J. Julian Blow ◽  
Inke Näthke
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Small Intestine ◽  
Intestinal Stem Cells ◽  
G1 Phase ◽  
Temporal Window ◽  
Restriction Point ◽  
Origins Of Replication ◽  
Interphase Cells ◽  
Functional Restriction

During late mitosis and the early G1 phase, the origins of replication are licensed by binding to double hexamers of MCM2–7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2–7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2–7, but still expressed the MCM2–7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5+ stem cells are in an unlicensed state. This suggests that the elongated cell–cycle of intestinal stem cells is caused by an increased G1 length, characterized by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost in Apc-mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

scholarly journals Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells

2017 ◽  
Author(s):  
T.D. Carroll ◽  
I.P. Newton ◽  
Y. Chen ◽  
J.J. Blow ◽  
I. Näthke
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Replication ◽  
Intestinal Epithelium ◽  
Intestinal Stem Cells ◽  
Temporal Window ◽  
Restriction Point ◽  
Interphase Cells ◽  
Small Intestinal ◽  
Functional Restriction

ABSTRACTDuring late mitosis and early G1, replication origins are licensed for replication by binding to double hexamers of MCM2-7. Here, we investigate how licensing and proliferative commitment are coupled in the small-intestinal epithelium. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5(+) stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem-cells is caused by an increased G1 length, characterised by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost In Apc mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

Thermotolerance of mammalian cells is not induced near the restriction point of the G1 phase of the cell cycle

2006 ◽  
Vol 411 (1) ◽  
pp. 515-516
Author(s):  
A. A. Kudryavtsev ◽  
V. P. Lavrovskaya ◽  
O. A. Pivovarova ◽  
E. I. Lezhnev ◽  
L. M. Chailakhyan
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
G1 Phase ◽  
Restriction Point

scholarly journals MCPH1 inhibits condensin II during interphase by regulating its SMC2-kleisin interface

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Martin Houlard ◽  
Erin E Cutts ◽  
Muhammad S Shamim ◽  
Jonathan Godwin ◽  
David Weisz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Eukaryotic Cell ◽  
Regulatory Factor ◽  
Chromosomal Dna ◽  
Premature Chromosome Condensation ◽  
Linear Motif ◽  
Interphase Cells

The dramatic change in morphology of chromosomal DNAs between interphase and mitosis is one of the defining features of the eukaryotic cell cycle. Two types of enzymes, namely cohesin and condensin confer the topology of chromosomal DNA by extruding DNA loops. While condensin normally configures chromosomes exclusively during mitosis, cohesin does so during interphase. The processivity of cohesin’s loop extrusion during interphase is limited by a regulatory factor called WAPL, which induces cohesin to dissociate from chromosomes via a mechanism that requires dissociation of its kleisin from the neck of SMC3. We show here that a related mechanism may be responsible for blocking condensin II from acting during interphase. Cells derived from patients affected by microcephaly caused by mutations in the MCPH1 gene undergo premature chromosome condensation but it has never been established for certain whether MCPH1 regulates condensin II directly. We show that deletion of Mcph1 in mouse embryonic stem cells unleashes an activity of condensin II that triggers formation of compact chromosomes in G1 and G2 phases, which is accompanied by enhanced mixing of A and B chromatin compartments, and that this occurs even in the absence of CDK1 activity. Crucially, inhibition of condensin II by MCPH1 depends on the binding of a short linear motif within MCPH1 to condensin II's NCAPG2 subunit. We show that the activities of both Cohesin and Condensin II may be restricted during interphase by similar types of mechanisms as MCPH1's ability to block condensin II's association with chromatin is abrogated by the fusion of SMC2 with NCAPH2. Remarkably, in the absence of both WAPL and MCPH1, cohesin and condensin II transform chromosomal DNAs of G2 cells into chromosomes with a solenoidal axis showing that both cohesin and condensin must be tightly regulated to adjust the structure of chromatids for their successful segregation.

scholarly journals Cell Cycle Analysis and Synchronization of Pluripotent Hematopoietic Progenitor Stem Cells

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2293-2299 ◽  
Author(s):  
G. Prem Veer Reddy ◽  
Cheryl Y. Tiarks ◽  
Lizhen Pang ◽  
Joanne Wuu ◽  
Chung-Cheng Hsieh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Calf Serum ◽  
S Phase ◽  
G1 Phase ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem

Abstract Hematopoietic stem cells purified from mouse bone marrow are quiescent with less than 2% of Lin− Hoechstlow/Rhodaminelow (Lin− Holow/Rholow) and 10% to 15% of Lin−/Sca+ cells in S phase. These cells enter proliferative cycle and progress through G1 and into S phase in the presence of cytokines and 5% heat-inactivated fetal calf serum (HI-FCS). Cytokine-stimulated Lin− Holow/Rholow cells took 36 to 40 hours to complete first division and only 12 hours to complete each of 5 subsequent divisions. These cells require 16 to 18 hours to transit through G0 /G1 period and 28 to 30 hours to enter into mid-S phase during the first cycle. Up to 56% of Lin− Rholow/Holow cells are high-proliferative potential (7 factor-responsive) colony-forming cells (HPP-CFC). At isolation, HPP-CFC are quiescent, but after 28 to 30 hours of culture, greater than 60% are in S phase. Isoleucine-deprivation of Lin−Holow/Rholow cells in S phase of first cycle reversibly blocked them from entering into second cycle. After the release from isoleucine-block, these cells exhibited a G1 period of less than 2 hours and entered into mid-S phase by 12 hours. Thus, the duration of G1 phase of the cells in second cycle is 4 to 5 times shorter than that observed in their first cycle. Similar cell cycle kinetics are observed with Lin−/Sca+ population of bone marrow cells. Stem cell factor (SCF ) alone, in the presence of HI-FCS, is as effective as a cocktail of 2 to 7 cytokines in inducing quiescent Lin−/Sca+ cells to enter into proliferative cycle. Aphidicolin treatment reversibly blocked cytokine-stimulated Lin−/Sca+ cells at G1 /S boundary, allowing their tight synchrony as they progress through first S phase and enter into second G1 . For these cells also, SCF alone is sufficient for their progression through S phase. These studies indicate a very short G1 phase for stem cells induced to proliferate and offer experimental approaches to synchronize murine hematopoietic stem cells.

Su1240 EXPANSION OF INTESTINAL STEM CELLS THROUGH CRYPT FISSION DURING POSTNATAL GROWTH OF THE SMALL INTESTINE

2020 ◽  
Vol 158 (6) ◽  
pp. S-555
Author(s):  
Zenab M. Dudhwala ◽  
Paul D. Hammond ◽  
Gordon S. Howarth ◽  
Adrian G. Cummins
Keyword(s):  
Stem Cells ◽  
Small Intestine ◽  
Postnatal Growth ◽  
Intestinal Stem Cells ◽  
Crypt Fission

scholarly journals Cyclin D activates the Rb tumor suppressor by mono-phosphorylation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Anil M Narasimha ◽  
Manuel Kaulich ◽  
Gary S Shapiro ◽  
Yoon J Choi ◽  
Piotr Sicinski ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Active Form ◽  
Biologically Active ◽  
G1 Phase ◽  
Cycle Progression ◽  
Restriction Point ◽  
Damage Response ◽  
E2f Transcription Factors

The widely accepted model of G1 cell cycle progression proposes that cyclin D:Cdk4/6 inactivates the Rb tumor suppressor during early G1 phase by progressive multi-phosphorylation, termed hypo-phosphorylation, to release E2F transcription factors. However, this model remains unproven biochemically and the biologically active form(s) of Rb remains unknown. In this study, we find that Rb is exclusively mono-phosphorylated in early G1 phase by cyclin D:Cdk4/6. Mono-phosphorylated Rb is composed of 14 independent isoforms that are all targeted by the E1a oncoprotein, but show preferential E2F binding patterns. At the late G1 Restriction Point, cyclin E:Cdk2 inactivates Rb by quantum hyper-phosphorylation. Cells undergoing a DNA damage response activate cyclin D:Cdk4/6 to generate mono-phosphorylated Rb that regulates global transcription, whereas cells undergoing differentiation utilize un-phosphorylated Rb. These observations fundamentally change our understanding of G1 cell cycle progression and show that mono-phosphorylated Rb, generated by cyclin D:Cdk4/6, is the only Rb isoform in early G1 phase.

907 Fasting Alters Cell Cycle Status in Both Rapidly and Slowly Cycling Intestinal Stem Cells

2012 ◽  
Vol 142 (5) ◽  
pp. S-159
Author(s):  
Camilla A. Richmond ◽  
Bristol Brandt ◽  
Diana L. Carlone ◽  
Robert K. Montgomery ◽  
David T. Breault
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Intestinal Stem Cells ◽  
Cell Cycle Status

The recruitability and cell-cycle state of intestinal stem cells

1984 ◽  
Vol 2 (2) ◽  
pp. 126-140 ◽  
Author(s):  
C. S. Potten ◽  
C. Chadwick ◽  
K. Ijiri ◽  
S. Tsubouchi ◽  
W. R. Hanson
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Intestinal Stem Cells

scholarly journals Intestinal stem cells contribute to the maturation of the neonatal small intestine and colon independently of digestive activity

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hirotsugu Yanai ◽  
Naho Atsumi ◽  
Toshihiro Tanaka ◽  
Naohiro Nakamura ◽  
Yoshihiro Komai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Small Intestine ◽  
Intestinal Stem Cells ◽  
Digestive Activity
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