Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action

Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction and fertility and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin a-subunit and by an activin binding protein, follistatin. The activin-BC subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-BC forms heterodimers with activin-BA and activin C antagonizes activin A in vitro. Thus, it is proposed that over-expression, rather than loss of activin-BC, regulates activin A bioactivity. In order to prove biological efficacy, inhibin a-subunit knockout mice (a-KO) were crossed with mice over-expressing activin-BC (ActC++). Deletion of inhibin leads to Sertoli and Granulosa Cell Tumours, increased activin A and cancer-associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in a-KO/ActC++ mice, where excessive activin A is the underlying cause. Accordingly, a reduction in activin A, no significant weight loss and reduced incidence of reproductive tumours was evident in a-KO/ActC++ mice. Over-expression of activin-Bc antagonised the activin signaling cascade thus, the tumourigenic effects of activin A were abrogated. This study provides proof of the biological relevance of activin-BC. Being a regulator of activin A it is able to abolish cachexia and modulate reproductive tumour development in a-KO mice. including development, reproduction and fertility and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin a-subunit and by an activin binding protein, follistatin. The activin-Bc subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-Bc forms heterodimers with activin-.......