Over recent years, a deeper comprehension of the molecular mechanisms that control biological clocks and circadian rhythms has been achieved. In fact, many studies have contributed to unravelling the importance of the molecular clock for the regulation of our physiology, including hormonal and metabolic homeostasis. Here we will review the structure, organisation and molecular machinery that make our circadian clock work, and its relevance for the proper functioning of physiological processes. We will also describe the interconnections between circadian rhythms and endocrine homeostasis, as well as the underlying consequences that circadian dysregulations might have in the development of several pathologic affections. Finally, we will discuss how a better knowledge of such relationships might prove helpful in designing new therapeutic approaches for endocrine and metabolic diseases.

Disorders of lipid and lipoprotein metabolism and transport are responsible for the development of a large spectrum of pathologies, ranging from cardiovascular diseases, to metabolic syndrome, even to tumour development. Recently, a deeper knowledge of the molecular mechanisms that control our biological clock and circadian rhythms has been achieved. From these studies it has clearly emerged how the molecular clock tightly regulates every aspect of our lives, including our metabolism. This review analyses the organisation and functioning of the circadian clock and its relevance in the regulation of physiological processes. We also describe metabolism and transport of lipids and lipoproteins as an essential aspect for our health, and we will focus on how the circadian clock and lipid metabolism are greatly interconnected. Finally, we discuss how a deeper knowledge of this relationship might be useful to improve the recent spread of metabolic diseases.

Mutations mimicking growth factor-induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel currently unknown players in these processes, we performed phosphoproteomic analysis on untransformed mammary epithelial cells (MCF10A) that were stimulated in culture with epidermal growth factor (EGF). We identified ladinin-1 (LAD1), a largely uncharacterized protein to date, as a phosphorylation-regulated mediator of the EGF-to-ERK pathway. Further experiments revealed that LAD1 mediated the proliferation and migration of mammary cells. LAD1 was transcriptionally induced, phosphorylated, and partly colocalized with actin stress fibers in response to EGF. Yeast two-hybrid, proximity ligation, and coimmunoprecipitation assays revealed that LAD1 bound to actin-cross-linking proteins called filamins. Cosedimentation analyses indicated that LAD1 played a role in actin dynamics, probably in collaboration with the scaffold protein 14-3-3σ (also called SFN). Depletion of LAD1 decreased the expression of transcripts associated with cell survival and inhibited the growth of mammary xenografts in an animal model. Furthermore, LAD1 predicts poor patient prognosis and is highly expressed in aggressive subtypes of breast cancer characterized as integrative clusters 5 and 10, which partly correspond to triple-negative and HER2-positive tumors. Thus, these findings reveal a cytoskeletal component that is critically involved in cell migration and the acquisition of oncogenic attributes in human mammary tumors.