Leandro Fernández-Pérez

By Leandro Fernández-Pérez, Amilcar Flores-Morales, Borja Guerra, Juan C. Díaz-Chico and Diego Iglesias-Gato

Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic development, adulthood, and aging. GHR belongs to a family of receptors without intrinsic kinase activity. However, GH binding to homodimers of GHR results in a conformational change in the receptors and the associated tyrosine kinase Janus kinase 2 (JAK2) molecules. Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues, and subsequent JAK2-dependent and JAK2-independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal reorganization, and lipid and glucose metabolism. JAK2 phosphorylates STAT5b, which is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism, and gender dimorphism; although STAT1, 3, and 5a have also been shown to be recruited by the GHR. In addition, many transcripts are regulated independently of STAT5b as a result of GHR activation of Src, ERK, and PI3K-mTOR signaling pathways. The analysis of molecular mechanisms involved in inactivation of GHR-dependent signaling pathway is also imperative for understanding GH physiology. This is clearly illustrated in the case of hepatic GHR-JAK2-STAT5b activation where signal duration regulates gender differences in liver gene expression. An early step in the termination of GH-dependent signaling is removal of GHRs by endocytosis and ubiquitination. The level of ubiquitin ligase SOCS2 is constitutively low, but its expression is rapidly induced by GH. SOCS2 binding to GHR complex promotes their ubiquitination and subsequent proteasomal degradation, contributing to the termination of the GH intracellular signaling. Clinically relevant, SOCS2 is a key negative regulator of GH-dependent body growth and lipid and glucose homeostasis. Furthermore, several cytokines, growth factors, xenobiotics, and sex hormones can regulate SOCS2 protein level, which provides a mechanism for cross-talking where multiple factors can regulate GHR signaling during somatic development. A better understanding of this complex regulation in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth and metabolic disorders.

Part of the book: Restricted Growth

By Carlota Recio, Haidée Aranda-Tavío, Miguel Guerra-Rodríguez, Mercedes de Mirecki-Garrido, Patricia Martín-Rodríguez, Borja Guerra and Leandro Fernández-Pérez

Janus kinases (JAKs) play an essential role in the regulation of cytokine signaling. They control cell survival, proliferation, differentiation, immune response, and hematopoiesis. Deregulation of JAK signaling has been associated to the pathogenesis of numerous immune-inflammatory diseases, hematological malignancies, and solid tumors. Thus, JAK proteins have emerged as attractive therapeutic targets in the last decade. The discovery of the gain-of-function JAK2 mutation (JAK2 V617F) as the main cause of polycythemia vera—a chronic myeloproliferative syndrome—led to the development of the JAK inhibitor ruxolitinib. This key finding opened the door to the search for new therapeutic agents able to suppress the constitutive activation of JAK signaling in hematological cancers and other tumors. However, given the conserved nature of the kinase domain among JAK family members, and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, the broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. This chapter focuses on the understanding of the complex signaling of JAK proteins in cancerous cells, the various JAK aberrations implicated in myeloproliferative neoplasms, leukemia, and lymphoma, and the clinically available JAK inhibitors in cancer therapy.

Part of the book: Tyrosine Kinases as Druggable Targets in Cancer

By Leandro Fernández-Pérez, Mercedes de Mirecki-Garrido, Carlota Recio and Borja Guerra

Sex steroids have important physiological actions, which are not limited to reproductive organs, in both females and males. They exert important physiological roles, including the regulation of somatotropic-liver axis, intermediate metabolism, or gender dimorphism. This is in part because the liver is a sex steroid-responsive organ where sex steroid- and growth hormone (GH)-dependent signaling pathways connect to regulate complex gene expression networks. Sex steroids can impact liver gene expression by a direct, through hepatic estrogen receptor (ER)α and androgen receptor (AR), or indirect mechanisms, by modulation of pituitary GH secretion and/or interaction with the GHR-STAT5b signaling pathway. Therefore, deficiency of sex steroid- and GH-dependent signaling pathways might cause a dramatic impact on mammalian liver physiology. In this chapter, we will focus our attention on main concepts and paradigms involved in the role and interplay between sex steroid- and GH-dependent signaling to regulate gene expression networks in the mammalian liver. A better understanding of how sex steroids and interactions with GH-STAT5b signaling pathway influence physiological and pathological states in the liver will contribute to improve clinical management of patients with disorders in body growth, development, and metabolism.

Part of the book: Chemistry and Biological Activity of Steroids

By José Manuel García-Castellano, David García-Padrón, Nerea Martínez-Aragón, Margarita Ramírez-Sánchez, Vicente Vera-Gutiérrez and Leandro Fernández-Pérez

Solid tumors, despite being hypervascularized, are hypoxic. This is due to the imbalance that exists between the inputs of the blood vessels that supply nutrients and O2 and that remove metabolic waste products, on one side; and the demands of the tumor cells that are part of the neoplasm that is forming, on the other. From this perspective, we briefly review the sequence of morphological events that occur during neo-angiogenesis; what chemical mediators are involved in this process; and we emphasize how the IL-6/Jak/Stat signaling pathway is involved in the control of these mediators. At the same time, we review how estrogens intervene in this control procedure, and how it opens the door to understanding the mechanism of action of these mediators. This would make it possible to propose alternative treatments, which can be added to the conventional ones, and which would exploit the findings described here in the search for new antitumor therapies.

Part of the book: Tumor Angiogenesis and Modulators

By José M. García-Castellano, Nerea Martínez-Aragón, David García-Padrón, Borja Guerra, Margarita Ramírez-Sánchez, Vicente Vera-Gutiérrez, Gerardo Garcés-Martín and Leandro Fernández-Pérez

Sarcomas are rare tumors that are difficult to treat. Many of them are chemo-resistant and with a high tendency to recur. Hence, finding new treatments is imperative in these tumors. Metabolic changes in tumor biology have become an essential characteristic in carcinogenesis processes, highlighting among them the role of lipids in these events, mainly cholesterol biosynthesis. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoAR), a key enzyme in the mevalonate pathway responsible for cholesterol synthesis, have an effect beyond the reduction in plasma cholesterol levels. These are the so-called pleiotropic effects of statins, responsible for some of the antitumor action of statins. Although there are considerable epidemiological and preclinical evidences that support the use of these medicaments in the treatment of sarcomas as adjuvant reprofiled drugs, clinical trials are disparate and heterogeneous, and do not provide enough information to help determine the convenience of their use, being necessary more studies to evaluate the efficacy and safety of statins in sarcomas. The purpose of this review is to update the role played by the reprofiled statins in the treatment of sarcomas.

Part of the book: Bone Tumours