KDM3A histone demethylase functions as an essential factor for activation of JAK2−STAT3 signaling pathway

Janus tyrosine kinase 2 (JAK2)−signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2−STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2−STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2−KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2−STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2−STAT3 signaling pathway.

Periplaneta Americana Extract May Attenuate Renal Fibrosis through Inhibiting Janus Tyrosine Kinase 2/Signal Transducer and Activator of Transcription 3 Pathway

Background: Periplaneta americana is one of the ancient insect groups with the strongest vitality. Periplaneta americana extract (PAE) has been explored as an alternative remedy for many diseases. Although much progress has been made in the study about PAE, the role of the drug in renal disease is rarely reported, especially in renal fibrosis. This study was designed to evaluate the renoprotective effect of PAE treatment to renal fibrosis. Method: An in vivo, unilateral ureteral obstruction (UUO) mouse model was built. Then the mice were treated with PAE (100 mg/kg body weight) once daily by oral gavage, again starting on the day of UUO and continued for 1 week. At the end of 1 week, the mice were sacrificed; kidney samples were collected for further analysis. In vitro, Boston University mouse proximal tubular cells were plated in 35-mm dishes at a density of 0.3 * 106 cells/dish. Then the cells were treated with 5-ng/mL TGF-β1 in serum-free DMEM medium for an indicated length of time. The experimental groups were pretreated with the indicated concentrations of PAE (0.3125 mg/mL). The cells were further cultured for 24 h, and then cells were monitored morphologically or collected for biochemical analyses. Results: Both in vivo and vitro PAE inhibits the expression of FN and alpha-smooth muscle actin and suppresses renal fibrosis. Importantly, PAE protects against renal fibrosis by inhibiting Janus tyrosine kinase 2 (JAK)/signal transducer and activator of transcription 3 (STAT) tyrosine phosphorylation. Conclusion: PAE attenuates renal fibrosis through the suppression of the JAK2/STAT3 pathway.

Tyrosyl Phosphorylated PAK1 Regulates Breast Cancer Cell Motility in Response to Prolactin through Filamin A

The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells.

Chronic Idiopathic Myelofibrosis: Clinicopathologic Features, Pathogenesis, and Prognosis

Context.—Chronic idiopathic myelofibrosis (CIMF) is a clonal myeloproliferative disease characterized by panmyelosis with intact maturation, progressive bone marrow fibrosis, and multiorgan extramedullary hematopoiesis. Objective.—This review article aims to summarize the recent updates regarding the clinicopathologic features, molecular pathogenesis, cytogenetic abnormalities, diagnostic criteria, new diagnostic ancillary tests, and prognostic factors of CIMF. Data Sources.—Important relevant articles indexed in PubMed/MEDLINE (National Library of Medicine) through the end of 2005 and referenced medical texts. Conclusions.—Because CIMF has a variety of clinical presentations, diagnosis may be challenging; the prefibrotic stage of CIMF has always been a challenging disease for pathologists to diagnose accurately. The recently proposed European Clinical and Pathological criteria can be helpful in the diagnosis of CIMF, especially in its prefibrotic stage. The enumeration of CD34-positive cells in the peripheral blood and the presence of circulating endothelial progenitor cells are the new important ancillary tests for the diagnosis of a small subset of patients with CIMF with atypical presentation. The recent discovery of the new mutation affecting the Janus tyrosine kinase 2 (JAK2V617F), more frequently observed in patients with polycythemia vera, is seen in approximately 35% to 57% of patients with CIMF. This mutation can serve as another diagnostic tool. Important factors affecting prognosis in CIMF are anemia, age of the patient, white blood cell count, degree of fibrosis, and number of blasts in the peripheral blood.