Journal of cellular signaling最新文献

PAX-interacting protein 1 (PTIP/PAXIP1) was discovered and initially characterized over three decades ago as a 1,056 amino acid-containing protein with six tandem BReast cancer C-Terminal (BRCT) repeats. PTIP functions broadly to catalyze histone methylation in DNA damage repair and within the hematopoietic lineage, to promote immunoglobulin variable region (variable, diversity, joining [VDJ]) and class switch recombination (CSR). In this report, we show that a fraction of PTIP is actively transported from the nucleus to mitochondria resulting in their aggregation, release of cytochrome c into the cytoplasm and cellular apoptosis. Deletion of an N-terminal glutamine-rich region (QR), mutation of a conserved threonine within BRCT3 and truncation of the C-terminal BRCT5 domain each significantly reduced apoptosis as well as its previously documented G₂/M cell cycle function. This is the first report to identify a mitochondrial-based apoptotic mechanism employed by the PTIP transcription factor.

Most malignantly transformed cells are metabolically rewired to promote their survival and progression, even under conditions that would be unfavorable for normal counterparts. Arguably the most impactful metabolic transformation and recognized cancer hallmark is the reprogrammed lipid metabolism. Lipids are not only primary constituents of cell membranes but essential participants in fundamental cellular functions including cell signaling, protein regulation, energy provision, inflammation, and cell-cell interaction. Engagement of lipids in critical physiological functions in cells is additionally accentuated upon malignant transformation. Pivotal roles of lipids as influential inter- and intracellular signaling molecules, particularly under conditions of hyper oxidative stress, are delineated. Elaborated in more detail are SCAP/SREBP pathway and sphingolipid signaling cascades due to their roles of principal signaling networks determining tumor therapy responses. In the concluding section, an overview is provided of the process of lipid peroxidation and its impact in cancer cells sustaining oxidative stress with the outline of cell signaling functions of primary and secondary lipid peroxidation products. Much remains to be learned about the consequences of the fact that the lipid peroxidation process can extend beyond the site of initiation owing to (either spontaneous or transfer protein-mediated) translocation of peroxy radical species disseminating their impact to other subcellular sites.

In an effort to clone polyglutamine-rich factors from activated B lymphocytes of mice, we discovered and describe here a previously uncharacterized isoform of PTIP/PAXIP1. By virtue of a two-nucleotide frameshift followed by alternative pre-mRNA splicing, this shorter isoform of 576 amino acids (termed PTIP576) retained only the two central BRCT domains of previously characterized PTIP and encodes a unique and structurally disordered 50 residue C-terminus. PTIP576 is expressed primarily in nuclei of progenitor and activated mature B lymphocytes. Transgenic overexpression of PTIP576 in murine B and T cells led to increased lineages of bone marrow B cells and thymocyte CD4 T cells. We conclude by addressing potential functions of PTIP576 resulting from the relatively unique mechanism by which it is engendered.

An increase in the temperature of lakes and ponds facilitates the over-growth of photosynthetic cyanobacteria that produce a class of toxins called cyanotoxins. The abundance of cyanobacteria poses a significant threat to drinking and irrigation water supplies, and therefore, cyanotoxins have become a major class of environmental pollutants. Microcystins, the most common cyanotoxins, are cyclic peptides produced by cyanobacteria through non-ribosomal peptide synthases, and currently, approximately 279 microcystins have been identified to date. Exposure to microcystins can cause liver and brain cytotoxicity, dermatologic, gastrointestinal, respiratory, and neurologic signs and symptoms, and affect human health. Notably, microcystin-leucine arginine can breach the blood-brain barrier by the transporter proteins, organic anion transporting polypeptides, leading to neuroinflammation, and changes in neurocircuitry resulting in behavioral alterations. In this review, we provide an update of the current literature on the detrimental effects of microcystins on the brain, focusing on their potential role in Alzheimer's and Parkinson's diseases. We discuss the current findings along with the cellular mechanisms involved and provide a brief narrative of the scope of future studies, especially to address the effects of microcystins along with genetic and other risk factors (like alcohol and other drugs) on neurodegenerative disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of end-stage renal disease. The disorder is primarily caused by pathogenic variants in PKD1 or PKD2, which encode the ciliary proteins polycystin-1 and polycystin-2. Loss of polycystin function disrupts calcium and cAMP signaling within the primary cilium, altering epithelial proliferation and fluid secretion that drive cyst formation and progressive kidney enlargement. Atypical forms of ADPKD arise from variants in genes required for the production of polycystins or for ciliary assembly. Cyst growth depends on proliferative and secretory pathways involving Ca²⁺, cAMP, mTORC1, Src, and receptor tyrosine kinases, while chloride and water transport via CFTR, ANO1, and NKCC1 drive luminal expansion. The vasopressin V2 receptor antagonists tolvaptan remains the only approved therapy, but new approaches are under investigation. These include inhibitors of mTORC1, Src, and RTKs, agents that block chloride secretion, small molecules and microRNAs that restore or enhance polycystin expression, and emerging cyst-directed cytotoxic therapies. By targeting aberrant epithelial responses to disrupted polycystin function, therapeutic intervention can be developed to halt cyst initiation, expansion, and progression to renal failure.

Fibroblast growth factors are signaling molecules that play crucial roles in fundamental processes such as cell migration, proliferation, differentiation, angiogenesis, and cell survival. FGFs signal by forming a complex with tyrosine kinase FGF receptors and cofactors. It is well known that FGFs play diverse roles in different tissues and at different developmental stages due to factors such as receptors, specific FGFs, and environmental conditions such as temperature and pH. This review focuses on the actions of mitogenic and metabolic FGFs and their interactions with their receptors to trigger their designated functions.

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib. The studies also identified hyaluronic acid synthase -3 (HAS3) as a bonafide target of Sorafenib in RCC cells. The studies demonstrate that an over-the-counter drug Hymecromone (4-methylumbelliferone) blocks inactivation of Sorafenib in RCC cells and improves its efficacy against mRCC through the inhibition of HAS3 expression and HA signaling. In the broader context, improving the efficacy of "old and failed drugs" that have favorable safety profiles should increase the availability of effective treatments for patients with advanced cancers.