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

Scott, Robert E.; Hoerl, Bryan J.; Wille, John J.; Florine, Dagne L.; Krawisz, Bruce R.; Yun, Kankatsu

doi:10.1083/jcb.94.2.400

Cited by 93 publications

(53 citation statements)

References 14 publications

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“…Furthermore, several genes that have been suggested to be involved in the control of the proliferative state of cells were downregulated, such as metastatic cell protein, drm (downregulated in mos-transformed cells), a 21-kDa peptide that is under translational control in tumor cells, hydrophobic nucleolar protein (HNP36), a large subunit of transforming growth factor (TGF)-␤ masking protein, gas 1 (growth-arrest specific gene 1), and a polypeptide having biological activity relating to proliferation and propagation of cells. This is, in most cases, well in agreement with previous findings indicating that differentiation of 3T3-L1 cells involves growth arrest (35) and that ligand-activated PPAR-␥ is sufficient to induce growth arrest (36). However, the downregulation of the large subunit of TGF-␤ masking protein, which neutralizes the activity of TGF-␤1, is surprising because TGF-␤1 has previously been shown to inhibit adipocyte differentiation (37).…”

Section: Resultssupporting

confidence: 79%

Novel Genes Regulated by the Insulin Sensitizer Rosiglitazone During Adipocyte Differentiation

et al. 2002

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Thiazolidinediones (TZDs) are a new class of compounds that improve insulin sensitivity in type 2 diabetic patients as well as in rodent models of this disease. These compounds act as ligands for a member of the nuclear hormone receptor superfamily, peroxisome proliferator-activated receptor-␥ (PPAR-␥), which is highly expressed in adipose tissue and, moreover, has been shown to play an important role in adipocyte differentiation. The strong correlation between the antidiabetic activity of TZDs and their ability to activate PPAR-␥ suggests that PPAR-␥, through downstream-regulated genes, mediates the effects of TZDs. In this report, we present the isolation and characterization of 81 genes, encoding proteins of known function, differentially expressed during TZDstimulated differentiation of 3T3-L1 cells. By the use of different reverse-Northern blot techniques, the differential expression of 50 of these genes could be verified, and 21 genes were specifically regulated by a potent TZD during the course of adipocyte differentiation, whereas no effect of a PPAR-␥ antagonist could be observed in mature adipocytes. The differential expression of a large fraction of the isolated genes was also shown to occur in white adipose tissue of ob/ob mice treated with rosiglitazone; combined, our results suggest that an important effect of rosiglitazone in adipose tissue is based on activation of PPAR-␥ in preexisting preadipocytes found among the mature adipocytes, resulting in subsequent adipocyte differentiation.

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Section: Resultssupporting

confidence: 79%

Novel Genes Regulated by the Insulin Sensitizer Rosiglitazone During Adipocyte Differentiation

et al. 2002

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“…The myc-sensitive point in G1 is reminiscent of the GD state that has been described for BALB/c 3T3 proadipocytes by Scott and co-workers (29,30,38). In this system, the growth arrest that immediately precedes terminal differentiation is postulated to occur at a point earlier in G1 than that seen with either serum deprivation or nutrient starvation.…”

Section: Discussionmentioning

confidence: 85%

c-myc antisense transcripts accelerate differentiation and inhibit G1 progression in murine erythroleukemia cells.

Prochownik¹,

Kukowska²,

Rodgers³

1988

Mol. Cell. Biol.

180

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Friend murine erythroleukemia (F-MEL) cells were transfected with a plasmid bearing tandemly arranged mouse c-myc antisense and dihydrofolate reductase transcription units. Sixteen clones were isolated, each containing unrearranged c-myc sequences and expressing high levels of antisense transcripts. All antisense clones examined contained reduced amounts of cytoplasmic endogenous c-myc transcripts. The kinetics of reaccumulation of endogenous c-myc mRNA during a 24-h exposure to dimethyl sulfoxide (DMSO) were also retarded and the ultimate transcript levels attained were less than in control cells. Antisense clones grew as well as control F-MEL cells in medium containing 10% fetal calf serum but at only a half and a quarter of the control rates in media containing 5 and 2% serum, respectively. Antisense clones differentiated faster and to a greater degree than control cells following DMSO exposure. myc antisense transcript expression was increased by growing cells in methotrexate, which resulted in an enhanced response to DMSO. Fluorescenceactivated cell sorter (FACS) analysis of cellular DNA content indicated that a greater fraction of antisense nuclei contained a GWG1 2n DNA content following a 24-h exposure to DMSO. When density-arrested antisense clones were diluted into fresh medium to allow reentry into the cell cycle, they incorporated less [31H]thymidine than control cells. FACS analysis showed that this was because only a portion of the cell population was entering S phase. Whereas control cells did not increase in size following release from density arrested antisense cels contained a subpopulation which were initially smaller and which eventually attained the same size as control cells. Quiescent antisense cells thus comprise two populations, each arrested at a different point in Gl.Dilutional replating allowed both populations to reenter the cell cycle. We propose a model which postulates that certain minimal myc levels are necessary for cells to traverse G1. Those with insufficient levels, due, for example, to antisense inhibition, are unable to completely traverse G1 during density arrest and synchronize at an earlier point than do control ceUs. This earlier point may be along the differentiation pathway and may account for the greater responsiveness of antisense cells to DMSO induction. This model postulates that F-MEL ceUs overexpressing myc fail to differentiate because myc levels are never sufficiently low enough to allow ceUs to enter the differentiation pathway.

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“…When cells were treated with dihydroteleocidin B after the induction stage, in which commitment had already taken place, a certain number of adipocytes was observed, although insulin no longer enhanced differentiation. Recently Scott et al (15) and Wille and Scott (21) suggested the existence of several substages in the adipocyte differentiation process under serum-containing conditions. They postulated a mechanism of re-initiation of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte differentiation of 3T3-L1 cells in serum-free hormone-supplemented media: Effects of insulin and dihydroteleocidin B.

Gamou

Shimizu

1986

Cell Struct. Funct.

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ABSTRACT. We previously established a serum-free hormone-supplemented medium for the induction of adipocyte differentiation of 3T3-L1 cells (Gamou, S. and N. Shimizu. in "Growth and Differentiation of Cells in Defined Environment", H. Murakami et al., ed., Kodansha/Springer-Verlag, pp. 173-178, 1985). Under those conditions the stage of the cell's commitment to adipocyte differentiation was separated from the stage of expression of the adipocyte phenotype. In the current study, the relationship between cell division of the growth-arrested 3T3-L1 cells and their entry into the differentiation program was examined by autoradiography at the individual cell level. It was found that cells treated with the inducers dexamethasone and 1-methyl-3-isobutylxanthine went through DNA synthesis (S phase) prior to lipid accumulation and that insulin enhanced this differentiation process. Under these serum-free hormone-supplemented conditions, the tumor promoter dihydroteleocidin B was found to be a strong inhibitor of adipocyte differentiation.A variant line of mouse Swiss/3T3 fibroblasts, 3T3-L1, is capable of differentiating into adipocytes (7). This differentiation can be synchronously induced at a high frequency by treating growth-arrested 3T3-L1 cells with dexamethasone (DEX) and 1-methyl-3-isobutylxanthine (MIX) (14). It has been shown that the growth arrest at a certain stage of the cell cycle plays an important role in the induction of cellular differentiation (6, 10, 16), and various factors appear to be involved in this process (2,8,9,12).We previously developed serum-free hormone-supplemented conditions under which the stage of the cells' commitment to adipocyte differentiation (Gc) can be separated from the stage of expression of the adipocyte phenotype (Gd) (6). The cells which were exposed to the inducers DEX and MIX for 48 h in medium lacking growth-promoting activity did not differentiate, but they did exhibit the adipocyte differentiation if serum was included in the medium during the expression stage. Thus, in 3T3-L1 cells, the commitment to differentiation seems to be elicited by the inducers without the cells going through the cell division cycle. However, DNA

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

Cited by 93 publications

References 14 publications

Novel Genes Regulated by the Insulin Sensitizer Rosiglitazone During Adipocyte Differentiation

Novel Genes Regulated by the Insulin Sensitizer Rosiglitazone During Adipocyte Differentiation

c-myc antisense transcripts accelerate differentiation and inhibit G1 progression in murine erythroleukemia cells.

Adipocyte differentiation of 3T3-L1 cells in serum-free hormone-supplemented media: Effects of insulin and dihydroteleocidin B.

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