Trends in endocrinology and metabolism

Boys, girls and shuttling of SRY and SOX9.

Publication Date: 2008 Aug PMID: 18585925
Authors: Sim, H. - Argentaro, A. - Harley, V. R.
Journal: Trends Endocrinol Metab

In the mammalian embryo, SRY and SOX9 are key Sertoli cell proteins that drive the development of the bipotential gonad into a testes rather than an ovary, leading ultimately to the male phenotype. Clinical SRY and SOX9 mutations causing disorders of sex development (DSD) highlight defective protein-protein interactions between SRY or SOX9, and carrier proteins required for nuclear import (importin-b and calmodulin) and nuclear export (CRM-1). The fine balance between import and export determines the levels of transcriptionally active SRY and SOX9 in the nucleus. Recently, post-translational modifications of SRY and SOX9 have been identified which affect nuclear transport. It is therefore timely that the consequences of sex-reversal mutation upon nuclear transport be reviewed. SRY and SOX9 mutations in DSD have uncovered regulatory sites for sumoylation, ubiquitination, acetylation and phosphorylation, many of which are essential for their transport and sex determining functions.

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IGF signaling defects as causes of growth failure and IUGR.

Publication Date: 2008 Aug PMID: 18515143
Authors: Klammt, J. - Pfaffle, R. - Werner, H. - Kiess, W.
Journal: Trends Endocrinol Metab

A substantial portion of children born small for gestational age (SGA) fail to catch up height, despite normal or even elevated insulin-like growth factor (IGF1) serum levels. In most cases, the etiology of the apparent IGF1 resistance is regarded as idiopathic. However, the recent identification of human IGF1 and IGF1 receptor (IGF1R) mutations, as well as information obtained from transgenic animals, points to a strong genetic component being of pivotal importance in the development of growth retardation. These findings direct attention to molecules downstream of the IGF1R, which have both growth-promoting and, to a lesser extent, metabolic functions. Therefore, defects in these molecules are likely to participate in the etiology of human SGA.

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PHLiPPing the switch on Akt and protein kinase C signaling.

Publication Date: 2008 Aug PMID: 18511290
Authors: Brognard, J. - Newton, A. C.
Journal: Trends Endocrinol Metab

The Ser/Thr-specific phosphatase PHLPP [pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase] provides 'the brakes' for Akt and protein kinase C (PKC) signaling. The two isoforms of this recently discovered family, PHLPP1 and PHLPP2, control the amplitude and duration of signaling of Akt and PKC by catalyzing the dephosphorylation of the hydrophobic phosphorylation motif, a C-terminal phosphorylation switch that controls these kinases. Aberrant regulation of either kinase accompanies many diseases, notably diabetes and cancer. By specifically dephosphorylating the hydrophobic motif, PHLPP controls the degree of agonist-evoked signaling by Akt and the cellular levels of PKC. This review focuses on the function of PHLPP1 and PHLPP2 in modulating signaling by Akt and PKC.

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Can menopausal hormone therapy prevent coronary heart disease?

Publication Date: 2008 Aug PMID: 18450469
Authors: Brinton, E. A. - Hodis, H. N. - Merriam, G. R. - Harman, S. M. - Naftolin, F.
Journal: Trends Endocrinol Metab

Observational studies show that women who take menopausal hormone therapy (MHT) have a greatly reduced risk of coronary heart disease (CHD). But in some large randomized controlled trials, MHT failed to decrease CHD and so has been deemed inappropriate for long-term prophylaxis against atherosclerosis or other chronic diseases associated with the menopause. Despite the apparent strength of this conclusion, several recent reports suggest that MHT could be atheroprotective when started close to the menopause, and effects of early discontinuation of MHT have never been studied in randomized trials. Here, we examine these reports and highlight existing uncertainty regarding the effects of long-term continuation versus early discontinuation of early-start MHT on atherosclerosis and CHD risk. We call for new research on this question, and an evidence-based review of existing recommendations for MHT.

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Immune-like mechanisms in ovulation.

Publication Date: 2008 Aug PMID: 18407514
Authors: Richards, J. S. - Liu, Z. - Shimada, M.
Journal: Trends Endocrinol Metab

Ovulation is the unique biological process by which a mature oocyte (egg) and surrounding somatic cells, the cumulus cell-oocyte complex (COC), are released from the surface of the ovary into the oviduct for transport and fertilization. Ovulation is similar to an inflammatory response: the follicles become hyperemic, produce prostaglandins and synthesize a hyaluronan-rich extracellular matrix. However, this view of ovulation might be too restrictive and needs to be broadened to encompass the innate immune cell surveillance-response system. This hypothesis is being proposed because ovarian granulosa cells and cumulus cells express and respond to innate immune cell-related surveillance proteins (Toll-like receptors 2 and 4) and cytokines, such as interleukin 6 (IL-6), during ovulation.

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