Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stressinduced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.
Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts.
Obesity has been described as a major factor of health risk in modern society. Next to intricately linked comorbidities like coronary artery disease or diabetes, an influence of obesity on regeneration after muscle injury has been described previously. However, the influence of obesity on tissue regeneration in a combined trauma, merging the more systemic influence of a blunt lung trauma and the local blunt muscle trauma, has not been investigated yet. Therefore, the aim of this study was to investigate the influence of obesity on regeneration in a mouse model that combined both muscle and thorax trauma. Using gene expression analysis, a focus was put on the structure as well as the organization of the extracellular matrix and on functional satellite cell physiology. An increased amount of debris in the lung of obese mice compared to normal weight mice up to 192 h after combined trauma based on visual assessment can be reported which is accompanied by a decreased response of Mmp2 in obese mice. Additionally, a delayed and elongated response of inhibitor genes like Timp1 has been revealed in obese mice. This elongated response to the trauma in obese mice can also be seen in plasma based on increased levels of pro-inflammatory chemo- and cytokines (IL-6, MCP-1, and IL 23) 192 h post trauma. In addition to changes in the lung, morphological analysis of the injured extensor iliotibialis anticus of the left hind leg in lean and diet-induced obese mice revealed deposition of fat in the regenerating muscle in obese animals hindering the structure of a compact muscle. Additionally, decreased activation of satellite cells and changes in organization and build-up of the ECM could be detected, finally leading to a decreased stability of the regenerated muscle in obese mice. Both factors contribute to an attenuated response to the trauma by obese mice which is reflected by a statistically significant decrease in muscle force of obese mice compared to lean mice 192 h post trauma induction.
Background Previously, it has been shown that obesity is a risk factor for recovery, regeneration, and tissue repair after blunt trauma and can affect the rate of muscle recovery and collagen deposition after trauma. To date, lung tissue regeneration and extracellular matrix regulation in obese mice after injury has not been investigated in detail yet. Methods This study uses an established blunt thorax trauma model to analyze morphological changes and alterations on gene and protein level in lean or obese (diet-induced obesity for 16 ± 1 week) male C57BL/6 J mice at various time-points after trauma induction (1 h, 6 h, 24 h, 72 h and 192 h). Results Morphological analysis after injury showed lung parenchyma damage at early time-points in both lean and obese mice. At later time-points a better regenerative capacity of lean mice was observed, since obese animals still exhibited alveoli collapse, wall thickness as well as remaining filled alveoli structures. Although lean mice showed significantly increased collagen and fibronectin gene levels, analysis of collagen deposition showed no difference based on colorimetric quantification of collagen and visual assessment of Sirius red staining. When investigating the organization of the ECM on gene level, a decreased response of obese mice after trauma regarding extracellular matrix composition and organization was detectable. Differences in the lung tissue between the diets regarding early responding MMPs (MMP8/9) and late responding MMPs (MMP2) could be observed on gene and protein level. Obese mice show differences in regulation of extracellular matrix components compared to normal weight mice, which results in a decreased total MMP activity in obese animals during the whole regeneration phase. Starting at 6 h post traumatic injury, lean mice show a 50% increase in total MMP activity compared to control animals, while MMP activity in obese mice drops to 50%. Conclusions In conclusion, abnormal regulation of the levels of extracellular matrix genes in the lung may contribute to an aberrant regeneration after trauma induction with a delay of repair and pathological changes of the lung tissue in obese mice.
Colon and rectal cancer (CRC) represents the fourth leading cause of cancer related deaths among all neoplastic diseases. Dysregulation of expression and/or kinase activity of CK1 isoforms can be linked to tumorigenesis and oncogenic mutations in CK1 have previously been found in CRC patients. Therefore, inhibition of overexpressed or mutated CK1 isoforms is supposed to have promising potential for the treatment of CRC. In order to detect further hyperactive and potentially oncogenic CK1 mutants we first analyzed the kinetic properties of several CK1δ mutants, which have been reported in different tumor entities. In subsequent experiments, we aimed at identifying small molecule inhibitors able to inhibit wild type and CK1δ mutants and to affect the growth of established (tumor) cell lines either expressing wild type or mutant CK1δ. In addition to well-established inhibitors of CK1 also newly developed compounds were tested, which are based on previously characterized IWP compounds ("inhibitors of Wnt production"). Among the tested molecules, inhibitors demonstrating CK1 isoformspecific as well as mutant-specific effects could be detected. Therefore, our results represent a starting point for further optimization approaches in the development of highly effective and specific CK1-targeting small molecule inhibitors.
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