Question

1. what are the effects of the environment on cell growth?

Answer 1

Cells from multicellular organisms are dependent upon exogenous signals for survival, growth, and proliferation. The relationship among these three processes was examined using an interleukin-3 (IL-3)-dependent cell line. No fixed dose of IL-3 determined the threshold below which cells underwent apoptosis. Instead, increasing growth factor concentrations resulted in progressive shortening of the G1 phase of the cell cycle and more rapid proliferative expansion. Increased growth factor concentrations also resulted in proportional increases in glycolytic rates. Paradoxically, cells growing in high concentrations of growth factor had an increased susceptibility to cell death upon growth factor withdrawal. This susceptibility correlated with the magnitude of the change in the glycolytic rate following growth factor withdrawal. To investigate whether changes in the availability of glycolytic products influence mitochondrion-initiated apoptosis, we artificially limited glycolysis by manipulating the glucose levels in the medium. Like growth factor withdrawal, glucose limitation resulted in Bax translocation, a decrease in mitochondrial membrane potential, and cytochromec redistribution to the cytosol. In contrast, increasing cell autonomous glucose uptake by overexpression of Glut1 significantly delayed apoptosis following growth factor withdrawal. These data suggest that a primary function of growth factors is to regulate glucose uptake and metabolism and thus maintain mitochondrial homeostasis and enable anabolic pathways required for cell growth. Consistent with this hypothesis, expression of the three genes involved in glucose uptake and glycolytic commitment, those for Glut1, hexokinase 2, and phosphofructokinase 1, was found to rapidly decline to nearly undetectable levels following growth factor withdrawal.

Tissue homeostasis in multicellular organisms is attained by a balance between the rate of cell proliferation and that of cell death. The competition for limiting amounts of exogenous factors has been shown to regulate cell proliferation, growth, and survival, and this competition has been proposed as a mechanism to determine tissue size (5, 16). The extracellular environment of most cells within a multicellular organism contains an ample supply of nutrients. Under physiological conditions, cell growth and proliferation are not limited by the extracellular availability of resources. It has been proposed that bioenergetics are not directly coupled to most cellular processes but are instead regulated homeostatically to maintain a steady-state ATP/ADP ratio. However, several papers documenting declines in cellular ATP/ADP ratios and in mitochondrial potential suggest that cells fail to maintain either ATP production or electron transport in the absence of growth factors (17, 22, 26).

Most evidence points to the mitochondria as the site of apoptosis initiation in response to growth factor withdrawal. Loss of integrity in the outer mitochondrial membrane leads to redistribution of cytochrome c into the cytosol, where it forms a caspase 9-activating complex in association with Apaf-1 and dATP (13). The molecular mechanisms by which outer mitochondrial membrane integrity is compromised remain controversial. Antiapoptotic Bcl-2 proteins, such as Bcl-xL, facilitate continued metabolite exchange across the outer mitochondrial membrane, prevent cytochrome c release, and promote cell survival despite the declines in ATP/ADP ratios and in mitochondrial potential that accompany growth factor withdrawal (22). In contrast, proapoptotic Bcl-2 proteins, such as Bax, have been reported to translocate to the mitochondria, impairing mitochondrial function and promoting cytochrome c release.

Control of cell survival by growth factors may be achieved either through the inhibition of apoptosis or through the active promotion of cell survival. Extensive work has documented that growth factors inhibit the activation of proapoptotic factors. However, the molecular mechanisms by which growth factors can promote cell survival are less well understood. Here, we report that growth factors require sustained glucose metabolism to promote cell survival. Reductions in growth factor availability result in coordinate decreases in cell size and glycolysis and increases in cell cycle time. Surprisingly, cells growing in low concentrations of growth factors are less sensitive to cell death induced by growth factor withdrawal. The ability of cytokines to rescue cells from death upon interleukin-3 (IL-3) withdrawal correlates with the ability to sustain glycolysis. Limiting glucose availability restricts the ability of growth factors to maintain cellular viability and results in cell death. Cell death caused by reduced availability of glucose is initiated by mitochondrial changes that result in cytochrome c release, events that resemble the commitment to cell death following growth factor withdrawal. The expression of Bcl-xL promotes cell survival through its ability to promote continued mitochondrial function, despite an otherwise lethal decrease in glycolysis. The overexpression of Glut1 can significantly delay the onset of apoptosis in response to growth factor withdrawal, indicating that intracellular glucose availability is an important determinant in the commitment to programmed cell death. Furthermore, we find that the failure of cells to maintain an effective mitochondrial potential in response to growth factor withdrawal results from a decline in the availability of electron transport substrates and coincides with a decline in the expression of the genes that control glucose uptake and glycolytic commitment. Thus, in the absence of growth factors, it appears that IL-3-dependent cells are unable to take up sufficient nutrients to maintain bioenergetic homeostasis.

Answer 2

medal ?

Answer 3

thank you!

Answer 4

Cite your sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC87309/