Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found i...Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.展开更多
Purpose： To investigate the potential correlation between two different types of hip fractures and serum calcium levels. Methods： We consecutively studied 101 cases of femoral neck fracture and 95 cases of femoral i...Purpose： To investigate the potential correlation between two different types of hip fractures and serum calcium levels. Methods： We consecutively studied 101 cases of femoral neck fracture and 95 cases of femoral inter- trochanteric fracture between January 2011 and December 2013. Fasting blood samples were taken and serum calcium measurements were performed respectively in three periods： the time of admission, postoperation, and discharge. Creatinine, alkaline phosphatase and albumin were also analyzed. Results： Considering the levels of serum calcium between two groups at the time of admission, post- operation and discharge, there was significant difference at admission and discharge （p 〈 0.05）, while there was no significant difference at the time of postoperation （p 〉 0.05）. The magnitude of serum calcium fluctuation was larger in femoral neck group than femoral intertrochanteric group. Concerning alkaline phosphatase and albumin levels at admission, there was no significant difference between two groups （p 〉 0.05）. Conclusion： The capability of reservation and restoration of serum calcium in patients with femoral neck fracture is better than that in patients with femoral intertrochanteric fracture. A low serum calcium level may be susceptible to femoral intertrochanteric fracture.展开更多
基金the National Key R&D Program of China(No.2016YFA0501800 to D.Y.2016YFC1303303 to C.Y.)+5 种基金the NSFC Grant(No.31871431 and No.31821002 to D.Y.81572761,81772655 and 81972646 to Y.T.)the Innovative Research Team of High-Level Local Universities in Shanghai(to D.Y.)the Recruitment Program of Global Experts of China(Y.T.)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(V.T.)Shanghai Rising-Star Program(Y.T.).
文摘Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
文摘Purpose： To investigate the potential correlation between two different types of hip fractures and serum calcium levels. Methods： We consecutively studied 101 cases of femoral neck fracture and 95 cases of femoral inter- trochanteric fracture between January 2011 and December 2013. Fasting blood samples were taken and serum calcium measurements were performed respectively in three periods： the time of admission, postoperation, and discharge. Creatinine, alkaline phosphatase and albumin were also analyzed. Results： Considering the levels of serum calcium between two groups at the time of admission, post- operation and discharge, there was significant difference at admission and discharge （p 〈 0.05）, while there was no significant difference at the time of postoperation （p 〉 0.05）. The magnitude of serum calcium fluctuation was larger in femoral neck group than femoral intertrochanteric group. Concerning alkaline phosphatase and albumin levels at admission, there was no significant difference between two groups （p 〉 0.05）. Conclusion： The capability of reservation and restoration of serum calcium in patients with femoral neck fracture is better than that in patients with femoral intertrochanteric fracture. A low serum calcium level may be susceptible to femoral intertrochanteric fracture.
