Conditions Determining Initiation of DNA Synthesis in 3T3 Cells
01 May 1970-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 66, Iss: 1, pp 204-210
TL;DR: The results show that topographical relationships between cells play an important role in controlling initiation of DNA synthesis and it is still unclear whether initiation is promoted by release from contacts or by the increased ability of the cells to utilize serum factors because of their changes in shapes and activities.
Abstract: Experiments were designed to discriminate between inhibition of growth due to contacts or exhaustion of serum factors. The cell layer was wounded and the migrating cells were followed by time-lapse cinematography; DNA synthesis in the same cells was recognized by means of 3H-thymidine labeling and radioautography. In this way, the complete history of individual cells migrating to the wound could be described. The results show that topographical relationships between cells play an important role in controlling initiation of DNA synthesis. It is still unclear whether initiation is promoted by release from contacts or by the increased ability of the cells to utilize serum factors because of their changes in shapes and activities.
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TL;DR: Cell shape was found to be tightly coupled to DNA synthesis and growth in nontransformed cells, suggesting a mechanism that is important in growth control of mammalian cells, and providing a more fundamental interpretation of such phenomena as density dependent inhibition of cell growth and anchorage dependence.
Abstract: Tissue culture plastic adhesivity was precisely varied by applying different concentrations of poly(2-hydroxyethyl methacrylate). The extent of cell spreading was thus accurately controlled so that cells cultured on these substrata could be held at any one of a graded series of quantitated cell shapes. Cell shape was found to be tightly coupled to DNA synthesis and growth in nontransformed cells. These findings suggest a mechanism that is important in growth control of mammalian cells, and provide a more fundamental interpretation of such phenomena as density dependent inhibition of cell growth and anchorage dependence.
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TL;DR: It is concluded that the factors that control growth are probably polypeptide hormones, or hormone-like materials, as well as a variety of low molecular weight nutrients.
Abstract: Recent studies of the control of growth of mammalian cells are considered and it is concluded that the factors that control growth are probably polypeptide hormones, or hormone-like materials, as well as a variety of low molecular weight nutrients. An understanding of the control of growth of mammalian cells will probably be found in the complex interactions of cells with these common types of materials.
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TL;DR: Use of a miniature pump to produce a local increase in velocity of medium across the surface of confluent 3T3 cells stimulates growth which is limited to the region of high velocity, indicating that growth is limited by a diffusion boundary layer close to the cell surface.
Abstract: Use of a miniature pump to produce a local increase in velocity of medium across the surface of confluent 3T3 cells stimulates growth which is limited to the region of high velocity. This indicates that growth is limited by a diffusion boundary layer close to the cell surface. The events at the edge of wounded cell layers (topoinhibition) can be explained by local variation in the fluid microenvironment rather than by alterations in contact between cells.
212 citations
TL;DR: Recent progress is discussed in elucidating the roles that cell-cell adhesion molecules play as receptors for CIP and in characterising the intracellular signaling pathways that mediate adhesion-dependent proliferative inhibition.
197 citations
Cites background from "Conditions Determining Initiation o..."
...Subsequent work concluded that this was not solely a consequence of growth factor exhaustion and was instead due to the ability of cell–cell adhesion to either directly or indirectly inhibit the response to serum growth factors [41]....
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TL;DR: PAK's ability to release human umbilical vein endothelial cells from contact inhibition is blocked by an unphosphorylatable form of its target Merlin, suggesting that PAK promotes mitogenesis by phosphorylating, and thus inactivating, Merlin.
Abstract: Introduction of activated p21-activated kinase (PAK) is sufficient to release primary endothelial cells from contact inhibition of growth. Confluent cells display deficient activation of PAK and translocation of Rac to the plasma membrane at matrix adhesions. Targeting Rac to the plasma membrane rescues these cells from contact inhibition. PAK's ability to release human umbilical vein endothelial cells from contact inhibition is blocked by an unphosphorylatable form of its target Merlin, suggesting that PAK promotes mitogenesis by phosphorylating, and thus inactivating, Merlin. Merlin mutants, which are presumed to exert a dominant-negative effect, enable recruitment of Rac to matrix adhesions and promote mitogenesis in confluent cells. Small interference RNA–mediated knockdown of Merlin exerts the same effects. Dominant-negative Rac blocks PAK-mediated release from contact inhibition, implying that PAK functions upstream of Rac in this signaling pathway. These results provide a framework for understanding the tumor suppressor function of Merlin and indicate that Merlin mediates contact inhibition of growth by suppressing recruitment of Rac to matrix adhesions.
191 citations
Cites background from "Conditions Determining Initiation o..."
...Normal cells cease to proliferate upon establishing cell–cell adhesions (Dulbecco and Stoker, 1970)....
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