Tgfbeta signaling in growth control, cancer, and heritable disorders

Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-beta type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-beta signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.

SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.

50 Years of Image Analysis

Anti-Mullerian hormone (AMH) is a member of the transforming growth factor-b superfamily, which plays an important role in both ovarian primordial follicle recruitment and dominant follicle selection in mice. However, the role of AMH in folliculo- genesis in humans has not been investigated in detail. In the present study, AMH expression was assessed using immunohisto- chemistry in ovarian sections, obtained from healthy regularly cycling women. To this end, a novel monoclonal antibody to human AMH was developed. AMH expression was not observed in primordial follicles, whereas 74% of the primary follicles showed at least a weak signal in the granulosa cells. The highest level of AMH expression was present in the granulosa cells of secondary, preantral and small antral follicles <4 mm in diameter. In larger (4-8 mm) antral follicles, AMH expression grad- ually disappeared. In conclusion, in the human AMH expression follows a similar pattern as compared to the mouse and rat, suggesting an important role of AMH in folliculogenesis.

Anti‐Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment

The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

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Ovarian surface epithelium: biology, endocrinology, and pathology.

Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti-Müllerian hormone and its type II receptor.

The role of anti-Müllerian hormone in gonadal development.

Male sex differentiation is driven by 2 hormones, testosterone and anti-mullerian hormone (AMH), responsible for the regression of mullerian ducts in male fetuses Mutations inactivating AMH or its receptor AMHRII lead to the persistent mullerian duct syndrome (PMDS) in otherwise normally virilized 46,XY males Our objective was to review the clinical, anatomical, and molecular features of PMDS based upon a review of the literature and upon 157 personal cases Three clinical presentations exist: bilateral cryptorchidism, unilateral cryptorchidism with contralateral hernia, and transverse testicular ectopia Abnormalities of male excretory ducts are frequent Testicular malignant degeneration occurs in 33% of adults with the disorder, while cancer of mullerian derivatives is less frequent Fertility is rare but possible if at least one testis is scrotal and its excretory ducts are intact Eighty families with 64 different mutations of the AMH gene have been identified, mostly in exons 1, 2, and 5 AMHRII gene mutations representing 58 different alleles have been discovered in 75 families The most common mutation, a 27-bp deletion in the kinase domain, was found in 30 patients of mostly Northern European origin In 12% of cases, no mutation of AMH or AMHRII has been detected, suggesting a disruption of other pathways involved in mullerian regression

/pdf/the-persistent-mullerian-duct-syndrome-an-update-based-upon-56hz7ul94s.pdf

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases.

In adulthood, the action of androgens on seminiferous tubules is essential for full quantitatively normal spermatogenesis and fertility. In contrast, their role in the fetal testis, and particularly in fetal germ cell development, remains largely unknown. Using testicular feminized (Tfm) mice, we investigated the effects of a lack of functional androgen receptor (AR) on fetal germ cells, also named gonocytes. We demonstrated that endogenous androgens/AR physiologically control normal gonocyte proliferation. We observed an increase in the number of gonocytes at 17.5 days postconception resulting from an increase in proliferative activity in Tfm mice. In a reciprocal manner, gonocyte proliferation is decreased by the addition of DHT in fetal testis organotypic culture. Furthermore, the AR coregulator Hsp90α (mRNA and protein) specifically expressed in gonocytes was down-regulated in Tfm mice at 15.5 days postconception. To investigate whether these effects could result from direct action of androgens on gonocytes, we collected pure gonocyte preparations and detected AR transcripts therein. We used an original model harboring a reporter gene that specifically reflects AR activity by androgens and clearly demonstrated the presence of a functional AR protein in fetal germ cells. These data provide in vivo and in vitro evidence of a new control of endogenous androgens on gonocytes identified as direct target cells for androgens. Finally, our results focus on a new pathway in the fetal testis during the embryonic period, which is the most sensitive to antiandrogenic endocrine disruptors.

Chrystèle Racine

Papers

Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti-Müllerian hormone and its type II receptor.

The role of anti-Müllerian hormone in gonadal development.

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases.

Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation

Luteinizing hormone-dependent activity and luteinizing hormone-independent differentiation of rat fetal Leydig cells.