China
Africa
Explore chapters and articles related to this topic
Nuclear Receptor Coactivators: Mechanism and Therapeutic Targeting in Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Andrew Cannon, Christopher Thompson, Rakesh Bhatia, Sushil Kumar
FHL2 is classically a membrane associated protein, but has also been reported to function as a transcriptional coactivator or corepressor of several receptors associated with cancer. In breast cancer, FHL2 overexpression was shown to increase the expression of p21 both in a cell cycle dependent manner and in response to treatment with doxorubicin [123]. FHL2-mediated p21 regulation occurred through the activation of AP-1 transcriptional complex. This upregulation of p21 prevented cell cycle progression through G2/M phase. Cell cycle arrest induction by FHL2 is consistent with an additional study that showed FHL2 is an interaction partner of BRCA1, although this study did not specifically explore the role of FHL2 with respect to DNA repair mechanisms [124]. Despite the role of FHL2 in cell cycle arrest, which suggests a role of FHL2 as a tumor suppressor, its expression in a non-malignant cell line derived from breast tissue showed that FHL2 expression increased the ability of cells to grow in adhesion independent conditions [123]. These findings indicate that FHL2 may have the potential to transform cells or alternatively play a role in tumor initiating cells. In addition to the role of FHL2 in cell cycle arrest in breast cancer cells, studies have suggested other roles for FHL2. With respect to antihormone resistance, Fan et al. showed that long-term culture of breast cancer cells in the absence of estrogens results in sensitization to the apoptosis induced by physiologic concentrations of estrogen [125]. Interestingly, this was shown to be mediated by c-SRC, and inhibition of c-SRC with concomitant estrogen treatment causes cell proliferation and ultimately the emergence of a population of cells that is proliferative in the presence of both tamoxifen and estrogen independent of estrogen receptor [125]. Analysis of this cell population showed that estrogen and tamoxifen treatment resulted in upregulation of several genes including an enrichment of genes associated with the cytoplasmic membrane including FHL2 [126]. The authors claim that this model is reminiscent of antiestrogen resistance in humans, and thus FHL2 is implicated as a putative mediator of this resistance phenotype; however; more detailed studies of the role of FHL2 in this setting are required before firm conclusions can be drawn [126]. Similarly, another study investigated FHL2 in terms of cytoskeletal dynamics. In this study, the partial knockdown of FHL2 reduced breast cancer cell invasion. The study went on to show that expression of full length, but not N- or C-terminal domains of MabP1, inhibited the pro-invasive activity of FHL2 [127]. Ultimately, the pro-invasive activity of FHL2 was tied to its localization at focal adhesions [127]. This finding is similar to those associated with other nuclear receptor coactivators, such as NCOA3, indicating that transcriptional activity may only be a part of the functional role of a nuclear receptor coactivator in physiology and disease.
Evaluating the influences of confounding variables on benchmark dose using a case study in the field of ionizing radiation
Published in International Journal of Radiation Biology, 2022
Nadine Adam, Ngoc Q. Vuong, Hailey Adams, Byron Kuo, Afshin Beheshti, Carole Yauk, Ruth Wilkins, Vinita Chauhan
In the Paul and Amundson (2011) study from which the transcriptional data being studied originates, 8 genes were identified that had altered expression between the smokers and nonsmokers, with only one transcript, FHL2, having been previously identified in the list of 289 radiation-responsive genes. FHL2 displayed a different dose-response relationship in smokers vs. nonsmokers (Paul and Amundson 2011). In the present study, the BMD value of FHL2 in female nonsmokers was higher (1.59 Gy) than in female smokers (0.30 Gy) (Table S1). The lower BMD value in female smokers suggests that this gene is activated at lower doses of gamma radiation in individuals who have previously been exposed to smoking particulate matter. Studies have shown that FHL2 expression is increased in disease states (Alnajar et al. 2013) and it may also be implicated in the radioresistance of pancreatic cancer cells (Scholl et al. 2000) and cell cycle dysregulation following regenerative stress in hematopoietic stem cells (Hou et al. 2015). Of note, FHL2 could not be modeled in male nonsmokers (Table S1). Specifically, it did not meet the filtering criteria of the Williams’ trend test (p-value < .05 and fold change > 1.5) filtering criterion due to the extreme variability in response between the individuals. This gene may thus warrant further focused studies to determine its status as a biomarker of radiation response in both males and females.
Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding
Published in Platelets, 2018
Marcus Fager Ferrari, Eva Leinoe, Maria Rossing, Eva Norström, Karin Strandberg, Tobias Steen Sejersen, Klaus Qvortrup, Eva Zetterberg
Familial Hemophagocytic Lymphohistiocytosis (FHL) is a rare, potentially life-threatening disorder characterized by a hyperinflammatory state due to a defective granule secretion in cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells [8]. Typical manifestations of FHL include prolonged fever, hepatosplenomegaly, cytopenias and coagulopathy [9]. Symptoms are usually evident within the first year of life [10], however, cases of adulthood onset are also described [11]. FHL is inherited in an autosomal recessive fashion and four different disease-causing genes have been identified: PFR1 (FHL2), UNC13D (FHL3), STX11 (FHL4) and STXBP2 (FHL5) [10]. Recently, variants in UNC13D, STX11 and STXBP2 have been shown to also affect platelet exocytosis.
A novel homozygous disruptive PRF1 variant (K285Sfs*4) causes very early-onset of familial hemophagocytic lymphohystiocytosis type 2
Published in Pediatric Hematology and Oncology, 2020
F. Saettini, I. Castelli, M. Provenzi, G. Fazio, M. Quadri, G. Cazzaniga, S. Sala, F. Dell’Acqua, E. Sieni, M. L. Coniglio, L. Pezzoli, M. Iascone, F. Vendemini, A. C. Balduzzi, A. Biondi, C. Rizzari, S. Bonanomi
In summary, in our patient FHL2 was caused by a unique, novel homozygous p.K285Sfs*4 variant resulting in very early-onset and fatal outcome. p.K285Sfs*4 leads to a premature stop codon in the MACPF domain of the perforin protein causing a presynaptic defect. FHL is a disease of early infancy and the effect of variants on the protein structure correlates with the early-onset of the disease. Evidence of a growing number of variants of the PRF1 gene and recognition of the broad phenotypic spectrum of FHL2 in humans indicate a crucial need to test the pathogenicity of each novel PRF1 gene variant individually.