Steroids, Insulin and Ecdysome in Cell Growth

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Glossary
Drosophila life cycle: embryo, larva (period of growth), pupa (period of maturation), adult;
20-Hydroxyecdysone (20E) - a steroid that controls the timing of developmental transitions and maturation and is produced by the
Prothoracic gland (PG) - a component of the ring gland of endocrine tissue;
EcR - 20E nuclear receptor;
IIS - insulin/IGF signaling system that functions through
InR - an insulin receptor that activates intracellular
PI3K - phosphatidylinositol-3-kinase - and the serine-threonine protein kinase Akt or PKB;
Fat body (FB) - the larval equivalent of the vertebrate liver and adipose tissue - the site of IIS and 20E activity
dFOXO - a transcription factor that must be dephosphorylated in order to be transported from the cytoplasm into the nucleus to stimulate transcription of
4E-BP - a gene whose product is an inhibitor of mRNA translation and protein synthesis.

In order to examine the basic mechanisms through which glucocorticoids may regulate cell growth, the investigators studied the role of 20E in the control of insect growth. They altered the production of 20E by the PG by “constructing” insects that expressed excessive wt PI3K or a dominant negative mutant - PI3K DN in their PG. In insects with excessive wt PI3K the size of PG was increased, while body size was decreased; insects expressing PI3K- DN had decreased PG size but increased body size. (There were no major differences in the duration of any developmental stage in the two insect lines.) Insects with wt PI3K synthesized more 20E, and PI3K-DN insects synthesized less 20E than did normal insects. Larval feeding of 20E reversed the growth promoting effects induced by PI3K-DN. Silencing of the 20E nuclear receptor increased the growth of insects. These data indicate that 20E inhibits larval growth rate but does not affect developmental timing. Larval feeding of 20E also decreased size of the FB and the activity of IIS - effects reversed by silencing expression of EcR. Consistent with increased IIS activity in PG-PI3K-DN insects, intracellular Akt activity was increased in these insects. PI3K and Akt hydroxylate and thereby prevent while 20 E facilitates transport of dFOXO from cytoplasm into nucleus. The dFOXO activates 4E-BP, a gene whose product inhibits protein translation. Thus, 20E impairs growth by antagonizing IIS action in the FB permitting increased nuclear transport of 4E-BP. The IIS acts in the PG to decrease 20E synthesis and in the FB to increase dFOXO phosphorylation thereby preventing its transport into the nucleus and consequently sustaining protein synthesis.

Colombani J, Bianchini L, Layalle S, et al. Antagonistic actions of ecdysone and insulins determine final size in Drosophila. Science. 2005;310:667–670.

Editor’s Comment

Glucocorticoids suppress growth by many mechanisms including depression of GH secretion, decreased expression of the GH receptor, inhibition of IGF-I action through lowering expression and binding of the IGF-I receptor, deceased chondrocyte proliferation and lowered rate of collagen synthesis.1 In the present paper, one molecular basis for inhibition of cellular growth has been elucidated, namely facilitation of the transport of the transcription factor dFOXO into the nucleus where it increases transcription of a factor that impairs mRNA translation and protein synthesis - activities that are the opposite of the growth-promoting effects of IIS. FOXO is the same transcription factor through which GH, insulin, and IGF-I regulate gluconeogenesis and fatty acid oxidation and thereby affect life span in a variety of species. 2,3

Allen W. Root, MD

Coordination of organism growth through insulin and ecdysone signaling. (Top) The four major stages of the Drosophila life cycle are depicted: embryonic, larval, pupal, and adult. Growth occurs during larval stages in response to insulin signaling and basal levels of the steroid hormone ecdysone. This is followed by sexual maturation during metamorphosis. (Bottom) The prothoracic gland releases ecdysone that activates the ecdysone receptor in fat body cells, producing an unknown factor X. This factor may suppress growth by inhibiting the release of insulin-like peptides from insulin-producing cells. Insulin-like peptides activate the insulin receptor and PI3K signaling pathway that blocks nuclear translocation of the transcription factor dFOXO. The ecdysone receptor may also induce expression of a factor Y that directs nuclear translocation of dFOXO, activating genes that inhibit growth, including that which encodes the 4E-BP protein translation inhibiton.

Reprinted with permission King-Jones K, Thummel CS. Science. 2005; 310:630–631. Copyright © 2005. Elsevier. All rights reserved.

References - (linked to Pubmed Links)

  1. Allen DB. Influence of inhaled corticosteroids on growth: a pediatric endocrinologist’s perspective. Acta Paediatr. 1998; 87:123–129.
  2. Saltiel AR. Putting the brakes on insulin signaling. N Engl J Med. 2003;349:2560.
  3. Bartke A. Minireview: Role of growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology. 2005;146:3718–3723.
  4. King-Jones K, Thummel CS. Developmental biology: Less steroids make bigger flies. Science. 2005; 310:630–631.

 

 

 


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