Effects of gravity on the cellular response to epidermal growth factor.
EGF and related polypeptides are involved in the regulation of cell growth and differentiation of continuously regenerating tissues, in tissue repair processes and in placental and fetal development. Their initial mode of action generally constitutes binding to specific plasma membrane localized receptors, transduction of the signal across the plasma membrane, subsequent activation of signalling pathways in the cell, and the induction of early nuclear gene expression. EGF-induced signal transmission from the plasma membrane to the nucleus has been studied in microgravity in order to gain insight in the molecular mechanisms that constitute the effects of gravity on cell growth. Exposure of human A431 cells to microgravity strongly suppresses EGF- and PMA-induced c-fos and c-jun expression. In contrast, forskolin- and A23187-induced c-fos expression and constitutive beta-2 microglobulin expression remain unaffected. This suggests that microgravity differentially modulates EGF-induced signal transduction pathways. Since both EGF and PMA are known to be activators of PKC, which is not the case for forskolin and A23187, PKC-mediated signal transduction may be a cellular target for microgravity. Inhibition of EGF-induced c-fos expression by microgravity occurs downstream of the initiation of EGF-induced signal transduction, i.e., EGF binding and EGFR redistribution. In addition to PKC signaling, actin microfilament organization appears to be sensitive to microgravity. Therefore, the inhibition of signal transduction by microgravity may be related to alterations in actin microfilament organization. The fact that early gene expression is affected by agents that alter the organization of the actin microfilament system supports this hypothesis. The decrease in c-fos and c-jun expression in microgravity may result in the decreased formation of the FOS and JUN proteins. Consequently, a short-term reduction in gene expression in microgravity may have a more dramatic effect over the long term, since both the JUN and FOS protein families are required for normal cell cycle progression. However, since more than 20 years of manned spaceflight have shown that humans can survive in microgravity for prolonged periods, it appears that cells in the human body can partly or completely overcome gravitational stress. Although some insight in the molecular basis on human cells has been obtained, future studies will be needed for a better understanding of the grounds for alterations in the cellular biochemistry due to altered gravity conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
Rijken
P J
PJ
Department of Molecular Cell Biology, University of Utrecht, The Netherlands.
Boonstra
J
J
Verkleij
A J
AJ
de Laat
S W
SW
D008841:Actin Cytoskeleton / Q000502:physiology; D000199:Actins / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D006112:Gravitation; D006801:Humans; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014893:Weightlessness
D000199:Actins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011493:Protein Kinase C