Relationship between Stat5b Expression in Cervical Tissues and Lesions / 中国医科大学学报

Objective To investigate the expression of signal transducer and activator of transcription 5 b (Stat5 b) and its phosphorylation (p-Stat5 b) in cervical lesions, its relationship with different degrees of cervical lesions, and its role in the pathogenesis and development of cervical lesions. Methods We obtained 80 specimens, including normal cervical tissues, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and cervical cancer tissues. To analyze the correlation between Stat5 b and the degree of cervical lesions, immunohistochemical staining was performed to detect Stat5 b and p-Stat5 b expression. Results Increased Stat5 b expression had a positive correlation with the development of cervical lesions. The percentages of Stat5 b expressed in normal tissues, LSIL, HSIL, and cervical cancer tissues were 15.0％, 0.0％, 50.0％, and 80.0％, respectively, with significant differences among the groups (P ＜ 0.05). Conversely, the expression of p-Stat5 b had a negative correlation with the development of cervical lesions.Expression of p-Stat5 b in normal tissues, LSIL, HSIL, and cervical cancer tissues was 80.0％, 45.0％, 5.0％, and 0.0％, respectively, with statistically significant differences among the groups (P ＜ 0.05). Conclusion The expression of Stat5 b is significantly different in different degrees of cervical lesions, suggesting that Stat5 b signaling molecules may be involved in the development of cervical lesions.

Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

Correlation of growth hormone receptor and its signal pathway defects with the phenotype: A study of 21 cases with growth hormone insensitivity syndrome / 中华内分泌代谢杂志

Objective To detect the relationship between the molecular defects and their phenotypes in children with growth hormone insensitivity syndrome (GHIS).Methods 21 patients defined as GHIS were enrolled in the study.4 candidate genes (GHR,IGFALS,JAK2,and STAT5B) were analyzed by genomic DNA sequence screening and clinical relevance analysis.Results The statistical descriptions of the patients were showed as an average height standard deviation (SDS)-4.33 ± 1.91 (-9.17 to-2.21),average serum peak values of GH (22.67 ±20.98) tg/L (11.33 to 104.21 μg/L),basal serum insulin-like growth factor-Ⅰ SDS-2.65 ± 0.53 (-3.57 to -1.79),insulin-like growth factor-binding protein 3 SDS-1.77 ± 1.64 (-4.13 to 0.96).Bone age of backward difference (chronological age-bone age) (43.10 ± 19.54) months (6 to 82 months).One of two children with severe growth failure and mid-face hypoplasia was found to a homozygote for G to A gene mutation in the intron 6 splice donor consensus sequences (IVS6 ds+ 1 G-A) in the GHR gene,causing its functional defect.3 cases with mild dwarf were found gene variations as novel finding:c.1097T＞C c.1098C＞T p.V366A pathogenic variant,c.1229C＞T p.S410L and nt1843707 A→G of 5' UTR region in the IGFALS gene.JAK2 and STAT5b genes mutations were not found.Conclusion Molecular pathology of GHIS is considered as involving the defects of GHR and its signal pathway.The mutation of intron 6 splice donor sequences in GHR gene has been reported which affect the function of GHR.The 3 novel type base variants in IGFALS gene,causing non severe dwarfism,might be suspected with pathogenic roles of GHIS.

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico / STAT5B deficiency: a new growth hormone insensitivity syndrome associated to immunological dysfunction

Uma nova apresentação da insensibilidade ao hormônio de crescimento (IGH), causada por mutações em homozigose no gene STAT5B (transdutor de sinal e ativador de transcrição tipo 5B), foi caracterizada nos últimos anos. Sua particularidade é a associação com quadros de disfunção imunológica grave, sendo o mais característico a pneumonite intersticial linfocítica. A presença concomitante de doenças crônicas imunológicas pode fazer com que a baixa estatura seja erroneamente considerada uma consequência do quadro clínico, levando ao subdiagnóstico dessa forma de IGH. O objetivo desta revisão é divulgar o conhecimento atual sobre essa rara patologia, facilitando o reconhecimento de pacientes com IGH secundária a mutações no gene STAT5B em ambulatórios de endocrinologia e de outras especialidades.

A new presentation of growth hormone insensitivity (GHI) caused by homozygous mutations in STAT5B (signal transducer and activator of transcription 5B) gene has been characterized in the last years. Its particularity is the association with severe immune dysfunction, especially with lymphocytic interstitial pneumonitis. This may mislead physicians into considering short stature as secondary to chronic immunological disease and consequently into underdiagnosing this form of GHI. The objective of this review is to propagate current knowledge about this rare pathology, facilitating the diagnosis of patients with GHI due to STAT5B mutations in endocrinology and other specialties clinics.

Differential Expression of STATs and Its Function in Osteogenesis of Mesenchymal Stem Cells / 대한정형외과연구학회지

PURPOSE: To investigate the role of STAT5 during osteogenesis differentiation of human mesenchymal stem cells(hMSC). MATERIALS AND METHODS: To assess the expression pattern of STATs during osteogenic differentiation, we performed western blot analysis and RT-PCR. By RNA interference, we have performed effect of STAT5A and STAT5B in osteogenesis. As a result of Luciferase assay, the promoter activity of DLX5 was decreased by STAT5A. RESULTS: To assess the expression pattern of STATs during osteogenic differentiation, we have performed western blot and RT-PCR after 14 day differentiation period. STAT1, 2, 3 and 4 showed no change in expression level during differentiation, while STAT5A and STAT5B displayed steady increase compared to the control. When STAT5A was knock down, the level of osteogenesis was increased. The transcriptional activity of DLX5 was decreased about 70% by STAT5A. CONCLUSION: The expression of STAT5A and STAT5B increased during osteogenesis of hMSC. Also, we shown that STAT5A regulated the transcriptional activity of DLX5. These results indicate that STAT5A acts as a pivotal transcription factor in osteogenesis of hMSC.

El receptor de la hormona de crecimiento humana (hGH) y la proteína de transporte de alta afinidad de la hGH / Human Growth Hormone (GH) Receptor and the High Affinity GH-Binding Protein

La hormona de crecimiento humana (hGH) circula parcialmente unida a su proteína de transporte de alta afinidad (GHBP) la cual resulta del clivaje proteolítico del dominio extracelular del receptor de GH. Recientemente la enzima TACE se identificó como la metaloproteasa responsable del clivaje y liberación de GHBP a circulación. Aunque aún se desconoce la función específica de esta proteína de transporte, distintos trabajos en la literatura demuestran efectos que potencian y efectos inhibitorios sobre la acción de GH. Por otro lado, existen evidencias que demuestran una fuerte relación entre la GHBP y el nivel de receptor de GH en el hígado en situaciones fisiológicas y patológicas. Esto permitió proponer a la determinación de GHBP en suero como un marcador periférico de la abundancia del receptor de GH en los tejidos. La determinación de la concentración de GHBP sería de especial interés para evaluar pacientes con diagnóstico probable de insensibilidad a la acción de GH y orientar el posterior estudio de anormalidades en el gen del receptor de GH. En la presente revisión, también se abordan dificultades metodológicas relacionadas a la medición de GHBP sérica.

Human circulating growth hormone (GH) is partly bound to a high-affinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Recently, the metalloproteinase TACE has been identified as an important enzyme responsive for inducing GHBP shedding. Although the specific function of GHBP is not fully known, both enhancing and inhibitory roles of this binding protein on GH action have been proposed. Many reports have demonstrated a close relationship between GHBP and the liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of the GH receptor abundance. Related to the latter, circulating GHBP concentration would be of special interest for the evaluation of GH insensitivity due to GH receptor gene abnormalities. In addition, the present review also focus on methodological problems concerning serum GHBP measurement.

Establishment of cell model for determining activity of insulin receptor kinase by STAT5b responsive reporter gene / 中国药理学通报

Aim To develop a simple and rapid method to monitor insulin receptor kinase activity and provide a novel cell-based model for screening anti-diabetes drugs.Methods CHO cells were co-transfected by plasmids which respectively contained insulin receptor gene,STAT5b gene and luciferase gene driven by STAT5 response elements.The expression of exogenous gene in transfected cells was examined by RT-PCR.The transfected cells were treated by insulin,and then the concentration and time-dependent response of luciferase expression to insulin induction was examined.Moreover,the specificity was identified by AG1024 treatment and PTP1B gene transfection.Results Expressions of insulin receptor and STAT5b were detected in the transfected CHO cells.The expression of luciferase in transfected cells was induced by insulin in concentration and time-dependent way.The maximal induction fold was 6.25.Moreover,the inducible expression of luciferase by insulin could be specifically blocked by tyrphostin AG1024,an inhibitor of insulin receptor kinase,or co-transfected PTP1B gene.Conclusions The insulin receptor kinase activity can be detected by expression of reporter gene with high sensitivity and specificity in this cell model,and with potential value in high throughput screening for insulin receptor activators and sensitizers.