Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. II. Tissue distribution of [125I]rh-inhibin A and [125I]rh-activin A in immature female and male rats.

Woodruff, Teresa K.; Krummen, Lynne A.; Chen, Sharon A.; Lyon, Rebecca; Hansen, Stanley E.; Deguzman, Geralyn E.; Covello, Robin; Mather, Jennie P.; Cossum, Paul A.

doi:10.1210/endo.132.2.8425491

Cited by 34 publications

(17 citation statements)

References 25 publications

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“…In addition, infusion of activin A into rats caused hepatocellular necrosis around the central vein of the liver (13). These physiologic effects of activin on hepatocytes are consistent with findings that a major site of 125I-labeled activin A binding is the rat liver (14) and that the type II activin receptor is expressed in the mouse liver (ref. 15; R. Towns and M.M.M., unpublished data).…”

Section: Introductionsupporting

confidence: 88%

“…Thus, inhibin can also function as a tumor suppressor in the adrenal cortex. Since previous studies have demonstrated that inhibin is produced in and can bind to the adrenal gland (14,(27)(28)(29) The differential temporal sensitivity of the adrenal and gonadal cells with respect to tumorigenesis is interesting. This might reflect other polypeptide hormones such as follicle-stimulating hormone or activin, which are upregulated in the absence of inhibin and may exert positive growth effects on only the gonadal cells (16,30).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Matzuk

Finegold

Mather

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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341

266

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Activins and inhibins, members of the tWe ( transforming growth factor superfamily of growth regulatory proteins, are produced in multiple tissues and affect diverse physiologic processes. Using embryonic stem cell technology, we previously demonstrated that inhibin can function as a gonadal tumor suppressor. In this study, we show that development of gonadal tumors is rapidly followed by a cancer cachexia-like wasting syndrome. Cachectic inhibin-deficient mice develop hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, are anemic, and demonstrate severe weight loss. The liver pathology is consistent with studies demonstrating an effect of elevated activins on rat hepatocytes. In inhibindeficient mice with tumors, activins are >10-fold elevated in the serum and are likely causing some of the cachexia symptoms. In contrast, inhibin-deficient mice gonadectomized at an early age do not develop this wasting syndrome. However, these gonadectomized, inhibin-deficient mice eventually develop adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland.The inhibins (a:(3 heterodimers) and activins (13:l3dimers) are related proteins that share common 13 subunits (either 13A or PB subunits) (1). These proteins, members of a large family of structurally related growth regulatory proteins, which includes the type (3 transforming growth factors (TGF-P), bone morphogenetic proteins, and Mullerian inhibiting substance (MIS) (1-4), have been shown to have diverse functions in a variety of assay systems including antiproliferative effects on carcinoma cell lines [i.e., MIS and TGF-p (2, 3)].The activins and inhibins also have diverse functions in mammalian physiology and development. Activin and inhibin subunit mRNAs and proteins are synthesized in a variety of cell types and embryonic and adult tissues in different species (1,(5)(6)(7)(8)(9)(10). In the adult mammal, although activins were initially discovered for their ability to stimulate pituitary follicle-stimulating hormone secretion, they have also been shown to influence other functions including liver metabolism and glucose regulation. For example, activin A can stimulate glycogenolysis (11) and inhibit DNA synthesis in isolated rat hepatocytes in vitro (12). In addition, infusion of activin A into rats caused hepatocellular necrosis around the central vein of the liver (13). These physiologic effects of activin on hepatocytes are consistent with findings that a major site of 125I-labeled activin A binding is the rat liver (14) and that the type II activin receptor is expressed in the mouse liver (ref. 15; R. Towns and M.M.M., unpublished data).Using embryonic stem cell technology, we have generated inhibin-deficient mice (16), which develop sex cord stromal tumors at an early age with nearly 1001% penetrance, demonstrating that inhibin functions in vivo as a tumor suppressor in the gonads of mice (16). In th...

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Section: Introductionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Matzuk

Finegold

Mather

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

341

266

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“…In rats, unilateral ovariectomy produces a transient increase in serum FSH but not LH. After 24 hours, there is a compensatory increase in inhibin subunit mRNA levels in the follicles of the remaining ovary (D'Agostino et al, 1989). Serum FSH and inhibin B levels are highly correlated across the rat estrous cycle .…”

Section: Physiological Regulation Of Inhibin Isoformsmentioning

confidence: 99%

“…For example, iodinated inhibin A, but not iodinated activin A, binds to rat Leydig cells . In addition, the adrenal, spleen, and bone marrow bind iodinated inhibin A at much higher levels than they bind iodinated activin A (Woodruff et al, 1993a). Gonadal tumors derived from inhibin a-subunit knockout mice bind iodinated inhibin A but bind iodinated activin A at much lower levels.…”

Section: Evidence For the Existence Of An Inhibin Receptormentioning

confidence: 99%

Mechanisms of Inhibin Signal Transduction

Bernard

Chapman²,

Woodruff³

2001

Recent Progress in Hormone Research

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Inhibin was first identified as a gonadal hormone that potently inhibits pituitary follicle-stimulating hormone (FSH) synthesis and secretion. Although the notion of a nonsteroidal, gonadally derived inhibitory substance was realized in the early 1930s (McCullagh, 1932) identification of the hormone was not accomplished until more than 50 years later. At that time, inhibin was purified from bovine and porcine follicular fluid and was shown to be produced in two forms through dimeric assembly of an Q subunit (I 8 kDa) and one of two closely related i3 subunits (PA and PB, approximately I4 kDa) Miyamoto et al., 1985;Rivier et al., 1985;Robertson et al., 1985).

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“…There is increasing evidence suggesting that activins are not only endocrine regulators of FSH availability but also potent effectors of autocrine or paracrine intraovarian signaling. Activin receptors and downstream Smad proteins are present in rat ovaries (22)(23)(24)(25)(26), and activins apparently play important roles in regulation of folliculogenesis and follicular function (27)(28)(29)(30). However, the knowledge about granulosa cells and how they respond to Smad signaling and its regulation is still rudimentary.…”

mentioning

confidence: 99%

Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Schmierer

Schuster

Shkumatava

et al. 2003

Journal of Biological Chemistry

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Activin A signaling is an important regulator of ovarian granulosa cell function. The cytosolic signal transducer Smad2 is most highly expressed in chicken granulosa cells (cGC) of preovulatory follicles. Moreover, Smad2 shows predominant nuclear localization in freshly isolated cGC, indicating active Smad signaling in vivo. Primary cGC cultured in vitro require activin A to sustain high Smad2 levels, which otherwise drop dramatically in the absence of activin A. This activin A-dependent Smad2 expression is abrogated by protein kinase A (PKA) inhibitors, suggesting a role for PKA in activin signaling. In the absence of activin A, strong PKA activators such as follicle-stimulating hormone (FSH) and 8-bromo-cyclic AMP fail to elicit Smad2 induction. However, FSH and 8-bromo-cyclic AMP boost activin A-dependent Smad2 up-regulation, giving rise to Smad2 levels similar to expression in vivo levels. Interestingly, the effect is specific for Smad2, since expression of the structurally and functionally closely related Smad3 remains entirely unaffected. Hence, activin A induces Smad2, but not Smad3, to high levels requiring PKA activation. Since Smad2 and Smad3 target distinct yet overlapping sets of TGF-␤/activin-responsive genes, the selective Smad2 induction by FSH/activin A could allow FSH to efficiently modulate the transcriptional readout of activin A signaling in avian granulosa cells.

show abstract

Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat. II. Tissue distribution of [125I]rh-inhibin A and [125I]rh-activin A in immature female and male rats.

Cited by 34 publications

References 25 publications

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.

Mechanisms of Inhibin Signal Transduction

Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

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