c-myb and growth control.

The available evidence indicates that c-myb plays an important role in the proliferation of hematopoietic cells and in those nonhematopoietic cell types in which c-myb is expressed. A critical aspect in the regulation of c-myb expression rests in the positive autoregulatory mechanism, which is dependent on the interaction of myb protein with the 5' flanking region of the human c-myb gene. The positive autoregulation of c-myb, in conjunction with tissue-specific mechanisms that most likely involve efficient transcription beyond the site of "transcriptional pause" in the c-myb first intron, might allow the generation of c-myb transcripts at levels sufficiently high for optimal biological activity (e.g., at the G1/S transition of the cell cycle). Other transactivating factors, such as the Jun family members, also appear to be involved in regulating c-myb expression. Such factors might act to increase basal levels of c-myb expression to allow activation of the autoregulatory mechanism, or might cooperate with myb in transcriptional regulation of c-myb expression. The function of c-myb is ultimately dependent on the genes that are regulated by the myb product. Preliminary evidence suggests that DNA polymerase-alpha and cdc2, two genes that are critical for DNA synthesis, contain myb binding sites in their promoter region that appear to be required for myb transactivation of their expression. The paradox of the generality of the mechanisms by which c-myb affects cell proliferation and the apparent tissue-specific expression of this gene might be resolved by the growing evidence that the tissue distribution of c-myb is more general than previously appreciated, and that many cell types with no detectable c-myb expression contain a functional equivalent of this gene. For example, B-myb a gene that is homologous to c-myb in the DNA binding and transactivating domains and appears to be ubiquitously expressed, is also required for cell proliferation and, like c-myb, appears to regulate the expression of cdc2, a gene required for cell cycle progression. Together, these findings indicate a general role of members of the myb family in regulation of cell proliferation

Bilateral adrenal incidentalomas and NR3C1 mutations causing glucocorticoid resistance: Is there an association?

Glucocorticoids signal through their cognate, ubiquitously expressed glucocorticoid receptor (GR), which influences the transcription of a large number of target genes. Several genetic defects, including point mutations, deletions or insertions in the NR3C1 gene that encodes the GR, have been associated with familial or sporadic generalized glucocorticoid resistance or Chrousos syndrome. One of the clinical manifestations of this rare endocrine condition is bilateral adrenal hyperplasia due to compensatory elevations of plasma ACTH concentrations. In this commentary, we discuss the interesting findings of the recently published French MUTA-GR study and present our perspective on the evolving field of NR3C1 pathology. © 2018 European Society of Endocrinology

Primary generalized glucocorticoid resistance and hypersensitivity syndromes: A 2021 update

Glucocorticoids are the final products of the neuroendocrine hypothalamic–pituitary— adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Sex differences in circadian endocrine rhythms: Clinical implications

Organisms have developed a highly conserved and tightly regulated circadian system, to adjust their daily activities to day/night cycles. This system consists of a central clock, which is located in the hypothalamic suprachiasmatic nucleus, and the peripheral clocks that are ubiquitously expressed in all tissues. Both the central and peripheral clocks communicate with each other and achieve circadian oscillations of gene expression through transcriptional/translational loops mediated by clock transcription factors. It is worth mentioning that circadian non-transcriptional/non-translational rhythms also occur in non-nucleated cells. Interestingly, sex has been identified as an important factor influencing the activity of the circadian system. Indeed, several sex differences have been documented in the anatomy, physiology and pathophysiology that pertain to circadian rhythms. In this review, we present the historical milestones of understanding circadian rhythms, describe the central and peripheral components of the circadian clock system, discuss representative examples of sexual dimorphism of circadian rhythms, and present the most relevant clinical implications. © 2020 Federation of European Neuroscience Societies and John Wiley & Sons Lt