Molecular and Cellular Endocrinology

Ubiquitin proteasome system (UPS) activation in the cardiac hypertrophy of hyperthyroidism Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Caroline Antunes Lino, Marilene Demasi, Maria Luiza Barreto-Chaves Abstract Ubiquitin proteasome system (UPS) is the main proteolytic pathway in eukaryotic cells. Changes in proteasome expression and activity have been associated to cardiovascular diseases as cardiac hypertrophy. Considering that cardiac hypertrophy is commonly associated to hyperthyroidism condition, the present study aimed to investigate the contribution of UPS in cardiac hypertrophy induced by thyroid hormones. Hyperthyroidism was induced in male Wistar rats by intraperitoneal injections of triiodothyronine (T3; 7  μg/100 g of body weight) for 7 days and confirmed by raised levels of total T3 and decreased levels of total T4. In addition, systolic blood pressure and heart rate were significantly increased in hyperthyroid group. Cardiac hypertrophy was confirmed in hyperthyroid group by increased heart weight/tibia length ratio and by increased α-MHC/β-MHC relative expression. Both catalytic (20SPT) and regulatory subunits (19SPT) of the constitutive proteasome were upregulated in hyperthyroid hearts. In addition, the transcripts that encode immunoproteasome subunits were also elevated. Furthermore, ATP-dependent chymotrypsin-like activity (26SPT) was significantly increased in hyperthyroid group. Despite the upregulation and activation of UPS in hyperthyroid hearts, the content of polyubiquitinated proteins was unaltered in relation to control. Together, these results evidence the activation of cardiac proteasome by thyroid hormones, which possibly contribute to the maintenance of protein quality control and regulation of cardiac hypertrophy in response to thyroid hormones.

Temperature alters the hypothalamic transcription of photoperiod responsive genes in induction of seasonal response in migratory redheaded buntings Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Amit Kumar Trivedi, Sayantan Sur, Aakansha Sharma, SK Tahajjul Taufique, Neelu Jain Gupta, Vinod Kumar Abstract We investigated the temperature effects on hypothalamic transcription of genes involved in the induction of photoperiodic response in redheaded buntings. Birds were exposed at 22 and 38 °C to 13-h long photoperiods (LP), with controls at 22 °C on 8-h short photoperiods (SP). At 22 °C, compared to SP, we found higher tshb, eya3 and dio2 and low dio3 and gnih mRNA expressions after a week of LP; concomitant with testis recrudescence this confirmed buntings' responsiveness to LP-induced photostimulation. tshb, dio2 and gnrh mRNA levels were further increased by 2.5 weeks of LP at 38 °C. Temperature sensitive trpm8, but not trpv4, bdnf or adcyap1 also showed LP-induced expression at 22 °C. Concomitant changes in dnmt3b and tet2 mRNA expressions further suggested epigenetic modification of temperature influence on photoperiodic responses. These results demonstrate the role of temperature in hypothalamic molecular regulation of the photoperiodic gonadal response in seasonally breeding birds.

Long non-coding RNA LINC01207 silencing suppresses AGR2 expression to facilitate autophagy and apoptosis of pancreatic cancer cells by sponging miR-143-5p Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Chang Liu, Jin-Ou Wang, Wen-Yang Zhou, Xiao-Ying Chang, Ming-Ming Zhang, Ying Zhang, Xiang-Hong Yang Abstract Pancreatic cancer is a serious malignancy accompanied by a well-documented poor prognosis. Accumulating studies have indicated the crucial roles played by long non-coding RNAs (lncRNAs) in proliferation, apoptosis and invasion of cancer cells. The aim of the current study was to investigate the role of lncRNA LINC01207 in autophagy and apoptosis of pancreatic cancer cells and its regulatory mechanism interacting with miR-143-5p. Initially, expression profiles of lncRNAs and genes associated with pancreatic cancer were identified. The expression patterns of LINC01207, miR-143-5p and AGR2 in both pancreatic cancer and adjacent tissues were then determined. The binding relationship of LINC01207 to miR-143-5p and targeting relationship of miR-143-5p to AGR2 were subsequently verified. Silencing of LINC01207, or up-regulation or down-regulation of miR-143-5p was introduced into the pancreatic cancer cells, so as to analyze their effects on the cell growth, apoptosis and autophagy. Besides, these regulatory effects were further explored with the determination of the autophagy- and apoptosis-related gene or proteins. LINC01207 and AGR2 were highly expressed while miR-143-5p was poorly expressed in pancreatic cancer. Functionally, LINC01207 can bind to miR-143-5p, and AGR2 was a target gene of miR-143-5p. Importantly, silencing of LINC01207 down-regulated the expression of AGR2 by up-regulating miR-143-5p. Moreover, silencing of LINC01207 and up-regulation of miR-143-5p promoted cell apoptosis and autophagy, corresponding to increased expression of autophagy- and apoptosis-related proteins, in addition to inhibited cell growth. Taken together, silencing of LINC01207 prevents the progression of pancreatic cancer by impairing miR-143-5p-targeted AGR2 expression, providing a potential target for pancreatic cancer treatment.

Characterization and differentiation of CD51+ Stem Leydig cells in adult mouse testes Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Panpan Chen, Xiaoju Guan, Xingxing Zhao, Fenfen Chen, Jianying Yang, Yiyan Wang, Yue Hu, Qingquan Lian, Haolin Chen Abstract It was reported previously that adult mouse stem Leydig cells (SLCs) express CD51 (integrin α-chain V). However, it is still unclear whether all CD51+ cells are SLCs. In the present study, we found that CD51+ cells can be classified into two sub-groups, a weakly-staining group (CD51+) and a strongly-staining group (CD51++). The CD51+ cells expressed common SLC marker genes, including Nestin, Pdgfra and Coup-tf2, while CD51++ cells did not express these genes. Instead, they expressed macrophage markers, such as F4/80, Cd115 and Tnfa. When these cells were induced to differentiate in vitro, the CD51+ cells, but not CD51++ cells, formed Leydig cells. Overall, our results showed that although SLCs expressed CD51, not all CD51-expressing cells are SLCs. The cells that expressed high levels of CD51 are actually macrophages.

Steroid receptor/coactivator binding inhibitors: An update Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Kornelia J. Skowron, Kenneth Booker, Changfeng Cheng, Simone Creed, Brian P. David, Phillip R. Lazzara, Amy Lian, Zamia Siddiqui, Thomas E. Speltz, Terry W. Moore Abstract The purpose of this review is to highlight recent developments in small molecules and peptides that block the binding of coactivators to steroid receptors. These coactivator binding inhibitors bind at the coregulator binding groove, also known as Activation Function-2, rather than at the ligand-binding site of steroid receptors. Steroid receptors that have been targeted with coactivator binding inhibitors include the androgen receptor, estrogen receptor and progesterone receptor. Coactivator binding inhibitors may be useful in some cases of resistance to currently prescribed therapeutics. The scope of the review includes small-molecule and peptide coactivator binding inhibitors for steroid receptors, with a particular focus on recent compounds that have been assayed in cell-based models.

Targeting Nuclear Receptors with PROTAC degraders Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): John J. Flanagan, Taavi K. Neklesa Abstract Nuclear receptors comprise a class of intracellular transcription factors whose major role is to act as sensors of various stimuli and to convert the external signal into a transcriptional output. Nuclear receptors (NRs) achieve this by possessing a ligand binding domain, which can bind cell permeable agonists, a DNA-binding domain, which binds the upstream sequences of target genes, and a regulatory domain that recruits the transcriptional machinery. The ligand binding alters the activation state of the NR, either by activating or inactivating its transcriptional output. Given the central role of NRs in signal transduction, many currently approved therapeutics modulate the activity of NRs. Here we discuss how PROTAC degraders afford a novel approach to abrogate the downstream signaling activity of NRs. We highlight six broad functional reasons why PROTAC degraders are preferable to the classical ligand binding pocket antagonists, with specific examples provided for each category. Lastly, as Androgen Receptor and Estrogen Receptor PROTAC degraders are being pursued as treatment for prostate cancer and breast cancer, respectively, a rationale is provided for the translational utility for the degradation of these two NRs.

Alternative ligands for thyroid hormone receptors Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Iván Lazcano, Gabriela Hernández-Puga, Juan Pablo Robles, Aurea Orozco Abstract Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that activate or repress gene transcription, resulting in the regulation of numerous physiological programs. While 3,3',5-L-triiodothyronine is the TR cognate ligand, these receptors can also be activated by various alternative ligands, including endogenous and synthetic molecules capable of inducing diverse active receptor conformations that influence thyroid hormone-dependent signaling pathways. This review mainly discusses current knowledge on 3,5-diiodo-L-thyronine and 3,5,3′-triiodothyroacetic acid, two endogenous molecules that bind to TRs and regulate gene expression; and the molecular interactions between TRs and ligands, like synthetic thyromimetics developed to target specific TR isoforms for tissue-specific regulation of thyroid-related disorders, or endocrine disruptors that have allowed the design of new analogues and revealed essential amino acids for thyroid hormone binding.

Role of adiponectin/peroxisome proliferator-activated receptor alpha signaling in human chorionic gonadotropin-induced estradiol synthesis in human luteinized granulosa cells Publication date: 1 August 2019 Source: Molecular and Cellular Endocrinology, Volume 493 Author(s): Tao Tao, Yuying Wang, Bing Xu, Xiuying Mao, Yun Sun, Wei Liu Abstract Impaired steroid production in polycystic ovary syndrome (PCOS) may result from adiponectin system dysfunction. However, adiponectin's role in ovulatory dysfunction remains unclear. We aimed to determine whether human chorionic gonadotropin (hCG) and adiponectin affect progesterone and estradiol secretion by granulosa cells (GCs) from overweight or obese women with PCOS or normal ovulation. ADIPOR2 expression was higher in hCG-treated GCs from PCOS patients than in those from normovulatory women. hCG may upregulate ADIPOR2 expression through cAMP/PKA signaling in GCs. GCs from both groups expressed PPARA. Estradiol levels were lower in hCG + adiponectin-treated GCs from PCOS patients than in those from normovulatory women. hCG + adiponectin decreased P450 aromatase expression through adiponectin/PPARα signaling in GCs. Adiponectin downregulates hCG-induced estradiol levels in GCs from overweight or obese women through gonadotropin–adiponectin crosstalk. Changes in gonadotropin and adiponectin signaling in the ovarian microenvironment may improve symptoms in women with PCOS.

Editorial Board Publication date: 15 June 2019 Source: Molecular and Cellular Endocrinology, Volume 490 Author(s):

Differential Expression of HMGA1 and HMGA2 in pituitary neuroendocrine tumors Publication date: 15 June 2019 Source: Molecular and Cellular Endocrinology, Volume 490 Author(s): Sérgio Portovedo, Nadja Gaido, Bruno de Almeida Nunes, Ana Giselia Nascimento, Allysson Rocha, Marcelo Magalhães, Gilvan Cortes Nascimento, Denise Pires de Carvalho, Paula Soares, Christina Takiya, Manuel dos Santos Faria, Leandro Miranda-Alves Abstract Defining biomarkers for invasive pituitary neuroendocrine tumors (PitNETs) is highly desirable. The high mobility group A (HMGA) proteins are among the most widely expressed cancer-associated proteins. Indeed, their overexpression is a frequent feature of human malignancies, including PitNETs. We show that nonfunctioning PitNETs (NF-PitNETs) express significantly higher levels of HMGA1 than somatotropinomas (GHs) and corticotropinomas (ACTHs). Furthermore, HMGA2 expression was detected only in NF-PitNETs and was significantly higher in larger tumors than in smaller tumors. HMGA expression analysis generally focuses on nuclear staining. Here, cytoplasmic HMGA staining was also found. PitNETs displayed strong nuclear HMGA1 and strong cytoplasmic HMGA2 immunoreactivity. Interestingly, the HMGA1 and HMGA2 nuclear expression levels were significantly higher in invasive adenomas than in noninvasive adenomas. The highest levels of nuclear HMGA2 were found in GHs. In conclusion, we show that overexpression of nuclear HMGA proteins could be a potential biomarker of invasive PitNETs, particularly HMGA2 for GHs. HMGA2 might be a reliable biomarker for NF-PitNETs.

Alexandros Sfakianakis
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alsfakia@gmail.com