Biomedical subjects

Bing Su

Publications and source records attributed to Bing Su.

At least 19 recordsLinked to original sources

PubMed2006

Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification.

Interleukin-1 (IL-1) receptor-associated kinase (IRAK) is phosphorylated after it is recruited to the receptor, subsequently ubiquitinated, and eventually degraded upon IL-1 stimulation. Although a point mutation changing lysine 134 to arginine (K134R) in IRAK abolished IL-1-induced IRAK ubiquitination and degradation, mutations of serines and threonines adjacent to lysine 134 to alanines ((S/T)A (131-144)) reduced IL-1-induced IRAK phosphorylation and abolished IRAK ubiquitination. Through the study of these IRAK modification mutants, we uncovered two parallel IL-1-mediated signaling pathways for NFkappaB activation, TAK1-dependent and MEKK3-dependent, respectively. These two pathways bifurcate at the level of IRAK modification. The TAK1-dependent pathway leads to IKKalpha/beta phosphorylation and IKKbeta activation, resulting in classical NFkappaB activation through IkappaBalpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylation and IKKalpha activation, resulting in NFkappaB activation through IkappaBalpha phosphorylation and subsequent dissociation from NFkappaB but without IkappaBalpha degradation. These results provide significant insight to our further understanding of NFkappaB activation pathways.

Animals↗

PubMed2006

The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway.

Members of the c-Jun NH(2)-terminal kinase (JNK) family play crucial roles in cell activation, differentiation, and apoptosis. Although many studies have indicated that JNK1 and JNK2 have functional differences and redundancy, the upstream signaling pathway that selectively activates JNK1 or JNK2 remains unknown. In this study, we have revealed a selective mechanism of JNK activation, in which JNK2, but not JNK1, was regulated by CARMA1, a scaffold molecule, after stimulation of the T cell receptor (TCR). This CARMA1-dependent regulation of JNK2 worked through the scaffold molecule Bcl10, which was inducibly associated with JNK2 and served as a JNK-interacting protein (JIP)-like scaffold to assemble the kinases JNK2, MKK7, and TAK1. Finally, we showed that CARMA1- and Bcl10-mediated JNK2 activation had a critical role in regulating the amount of c-Jun protein. Together, our studies provide genetic evidence that JNK1 and JNK2 are differentially regulated in the TCR-signaling pathway and play different functions.

Animals↗

PubMed2006

Comparison of Pax1/9 locus reveals 500-Myr-old syntenic block and evolutionary conserved noncoding regions.

Identification of conserved genomic regions within and between different genomes is crucial when studying genome evolution. Here, we described regions of strong synteny conservation between vertebrate deuterostomes (tetrapods and teleosts) and invertebrate deuterostomes (amphioxus and sea urchin). The shared gene contents across phylogenetically distant species demonstrate that the conservation of the regions stemmed from an ancestral segment instead of a series of independent convergent events. Comparison of the syntenic regions allows us to postulate the primitive gene organization in the last common ancestor of deuterostomes and the evolutionary events that occurred to the 3 distinct lineages of sea urchin, amphioxus, and vertebrates after their separation. In addition, alignment of the syntenic regions led to the identification of 8 noncoding evolutionarily conserved regions shared between amphioxus and vertebrates. To our knowledge, this is the first report of conserved noncoding sequences shared by vertebrates and nonvertebrates. These noncoding sequences have high possibility of being elements that regulate neighboring genes. They are likely to be a factor in the maintenance of conserved synteny over long phylogenetic distance in different deuterostome lineages.

Amino Acid Sequence↗

PubMed2006

Epidemiology, clinical and laboratory characteristics of currently alive HIV-1 infected former blood donors naive to antiretroviral therapy in Anhui Province, China.

BACKGROUND: Unregulated commercial blood/plasma collection among farmers occurred between 1992 and 1995 in central China and caused the second major epidemic of human immunodeficiency virus type 1 (HIV-1) infection in China. It is important to characterize HIV-1-infected former blood donors and to study characteristics associated with disease progression for future clinical intervention and vaccine development. METHODS: A cross-sectional study was performed on HIV-1-infected former blood donors (FBDs) and age-matched HIV-seronegative local residents. Demographic, epidemiologic, clinical and key laboratory data were collected from all study participants. Both unadjusted and adjusted multivariate linear regressions were employed to analyze the association of the decrease of CD4(+) T-cell counts with other characteristics. RESULTS: Two hundred and ninety-four HIV-1-infected FBDs and 59 age-matched HIV-seronegative local residents were enrolled in this study. The unregulated blood/plasma collection occurred more than a decade (10.8 - 12.8 years) ago, which caused the rapid spread of HIV-1 infection and the high prevalence of co-infection with hepatitis C virus (HCV, 89.5%); hepatitis B virus (HBV) co-infection was observed in only 11 HIV(+)participants (3.7%). Deterioration in both clinical manifestation and laboratory parameters and increase of viral loads were observed in parallel with the decrease of CD4(+) T-cell counts. The decrease of total lymphocyte counts (P < 0.001) and hemoglobin levels (P < 0.001) and the appearance of dermatosis (P = 0.03) were observed in parallel with the decrease of CD4(+) T-cell counts whereas viral loads (P < 0.001) and CD8(+) T-cell counts (P = 0.01) were inversely associated with CD4(+) T-cell counts. CONCLUSIONS: Co-infection with HCV but not HBV is highly prevalent among HIV-1-infected FBDs. CD4(+) T-cell counts is a reliable indicator for disease progression among FBDs. Total lymphocyte counts, hemoglobin level and appearance of dermatosis were positively associated with CD8(+) T-cell counts and viral loads were inversely associated with the decreased CD4(+) T-cell counts.

Adult↗

PubMed2006

MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages.

Mitogen-activated protein/ERK kinase kinase 3 (MEKK3) is a Ser/Thr protein kinase belonging to the MEKK/STE11 subgroup of the MAP3K family. Recently, we found that MEKK3 plays a critical role in interleukin-1 (IL-1) receptor and Toll-like receptor 4 signalling using established primary mouse embryonic fibroblast (MEF) cell lines. However, the function of MEKK3 in immune cells has not been studied because germ-line MEKK3 knockout mice are embryonically lethal between embryonic days 10 and 11. In this study, we used small interference RNA to the mouse Mekk3 gene to specifically knock down MEKK3 expression in the macrophage line Raw264.7. We found that the lipopolysaccharide-induced IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production was dramatically decreased in MEKK3 knockdown cells whereas the tumour necrosis factor-alpha and IL-1beta production were not affected. We also observed that the ERK1/2, p38 and JNK MAPK induction in MEKK3 knockdown cells were moderately inhibited within the first 60 min of stimulation, while the ERK and p38 were more severely inhibited after 2-4 hr of stimulation. Degradation of IkappaBalpha was also partially blocked in MEKK3 knockdown cells. Notably, the impairment in IL-6 and GM-CSF production in the MEKK3 knockdown cells was restored by reintroducing a human Mekk3 cDNA that could not be targeted by mouse Mekk3-siRNAs. In conclusion, this study showed that MEKK3 is a crucial and specific regulator of the proinflammatory cytokines IL-6 and GM-CSF in macrophages and provided a novel method for investigating MEKK3 function in other immune cells.

Animals↗

PubMed2006

Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade.

The extracellular signal-regulated kinase 5 (ERK5) is activated in neurons of the central nervous system by neurotrophins including brain-derived neurotrophic factor (BDNF). Although MEK5 is known to mediate BDNF stimulation of ERK5 in central nervous system neurons, other upstream signaling components have not been identified. Here, we report that BDNF induces a sustained activation of ERK5 in rat cortical neurons and activates Rap1, a small GTPase, as well as MEKK2, a MEK5 kinase. Our data indicate that activation of Rap1 or MEKK2 is sufficient to stimulate ERK5, whereas inhibition of either Rap1 or MEKK2 attenuates BDNF activation of ERK5. Furthermore, BDNF stimulation of MEKK2 is regulated by Rap1. Our evidence also indicates that Ras and MEKK3, a MEK5 kinase in non-neuronal cells, do not play a significant role in BDNF activation of ERK5. This study identifies Rap1 and MEKK2 as critical upstream signaling molecules mediating BDNF stimulation of ERK5 in central nervous system neurons.

Animals↗

PubMed2006

SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.

Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Genetic ablation of sin1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction but maintained Thr308 phosphorylation. Surprisingly, defective Ser473 phosphorylation affected only a subset of Akt targets in vivo, including FoxO1/3a, while other Akt targets, TSC2 and GSK3, and the TORC1 effectors, S6K and 4E-BP1, were unaffected. Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function.

Adaptor Proteins, Signal Transducing↗

PubMed2006

No accelerated evolution of 3'UTR region in human for brain-expressed genes.

The difference in cognitive skills between humans and nonhuman primates is one of the major characters that define our own species. It was previously hypothesized that this divergence might be attributable to genetic differences at gene expression level, and the cis-regulating elements of gene 3'UTRs might play important roles in the post-transcriptional regulation of gene expression. In this study, we constructed a cDNA library from the prefrontal cortex of rhesus monkey and generated a total of 754 high-quality ESTs. Using rhesus macaque as outgroup, we calculated the evolutionary rates of the 3'UTRs of 52 brain-expressed genes in humans and chimpanzees in order to dissect the role of natural selection during primate brain evolution. Comparison of 52 orthologous gene sequences of human and chimpanzee indicated that the mean substitution rates at nonsynonymous sites (K(a)), synonymous sites (K(s)) and 3'UTRs (K(3u)) are 0.0024, 0.0116 and 0.0117, respectively. Relative rate tests and acceleration index tests demonstrated that only a few genes had significant rate divergence between human and chimpanzee. The 3'UTRs of the brain-expressed genes in primates has a similar evolutionary rate with the synonymous sites of the gene coding region, indicating a neutral evolution of the 3'UTR sequences in human.

3' Untranslated Regions↗

PubMed2006

Detecting lineage-specific adaptive evolution of brain-expressed genes in human using rhesus macaque as outgroup.

Comparative genetic analysis between human and chimpanzee may detect genetic divergences responsible for human-specific characteristics. Previous studies have identified a series of genes that potentially underwent Darwinian positive selection during human evolution. However, without a closely related species as outgroup, it is difficult to identify human-lineage-specific changes, which is critical in delineating the biological uniqueness of humans. In this study, we conducted phylogeny-based analyses of 2633 human brain-expressed genes using rhesus macaque as the outgroup. We identified 47 candidate genes showing strong evidence of positive selection in the human lineage. Genes with maximal expression in the brain showed a higher evolutionary rate in human than in chimpanzee. We observed that many immune-defense-related genes were under strong positive selection, and this trend was more prominent in chimpanzee than in human. We also demonstrated that rhesus macaque performed much better than mouse as an outgroup in identifying lineage-specific selection in humans.

Adaptation, Biological↗

PubMed2006

A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing.

The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1) mediates activin B signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization.

Activins↗

PubMed2006

SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition.

SSeCKS, a Src-suppressed protein kinase C substrate with metastasis suppressor activity, is the rodent orthologue of human gravin/AKAP12, a scaffolding protein for protein kinase A and protein kinase C. We show here that the tetracycline-regulated reexpression of SSeCKS in MatLyLu (MLL) prostate cancer cells suppressed formation of macroscopic lung metastases in both spontaneous and experimental models of in vivo metastasis while having minimal inhibitory effects on the growth of primary-site s.c. tumors. SSeCKS decreased angiogenesis in vitro and in vivo by suppressing vascular endothelial growth factor (VEGF) expression in MLL tumor cells as well as in stromal cells. The forced reexpression of VEGF(165) and VEGF(121) isoforms was sufficient to reverse aspects of SSeCKS metastasis-suppressor activity in both the experimental and spontaneous models. SSeCKS reexpression in MLL cells resulted in the down-regulation of proangiogenic genes, such as osteopontin, tenascin C, KGF, angiopoietin, HIF-1alpha, and PDGFRbeta, and the up-regulation of antiangiogenic genes, such as vasostatin and collagen 18a1, a precursor of endostatin. These results suggest that SSeCKS suppresses formation of metastatic lesions by inhibiting VEGF expression and by inducing soluble antiangiogenic factors.

A Kinase Anchor Proteins↗

PubMed2006

TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent.

TLR8-mediated NF-kappaB and IRF7 activation are abolished in human IRAK-deficient 293 cells and IRAK4-deficient fibroblast cells. Both wild-type and kinase-inactive mutants of IRAK and IRAK4, respectively, restored TLR8-mediated NF-kappaB and IRF7 activation in the IRAK- and IRAK4-deficient cells, indicating that the kinase activity of IRAK and IRAK4 is probably redundant for TLR8-mediated signaling. We recently found that TLR8 mediates a unique NF-kappaB activation pathway in human 293 cells and mouse embryonic fibroblasts, accompanied only by IkappaBalpha phosphorylation and not IkappaBalpha degradation, whereas interleukin (IL)-1 stimulation causes both IkappaBalpha phosphorylation and degradation. The intermediate signaling events mediated by IL-1 (including IRAK modifications and degradation and TAK1 activation) were not detected in cells stimulated by TLR8 ligands. TLR8 ligands trigger similar levels of IkappaBalpha phosphorylation and NF-kappaB and JNK activation in TAK1(-/-) mouse embryo fibroblasts (MEFs) as compared with wild-type MEFs, whereas lack of TAK1 results in reduced IL-1-mediated NF-kappaB activation and abolished IL-1-induced JNK activation. The above results indicate that although TLR8-mediated NF-kappaB and JNK activation are IRAK-dependent, they do not require IRAK modification and are TAK1-independent. On the other hand, TLR8-mediated IkappaBalpha phosphorylation, NF-kappaB, and JNK activation are completely abolished in MEKK3(-/-) MEFs, whereas IL-1-mediated signaling was only moderately reduced in these deficient MEFs as compared with wild-type cells. The differences between IL-1R- and TLR8-mediated NF-kappaB activation are also reflected at the level of IkappaB kinase (IKK) complex. TLR8 ligands induced IKKgamma phosphorylation, whereas IKKalpha/beta phosphorylation and IKKgamma ubiquitination that can be induced by IL-1 were not detected in cells treated with TLR8 ligands. We postulate that TLR8-mediated MEKK3-dependent IKKgamma phosphorylation might play an important role in the activation of IKK complex, leading to IkappaBalpha phosphorylation.

Animals↗

PubMed2006

Origination and evolution of a human-specific transmembrane protein gene, c1orf37-dup.

A transmembrane protein gene, c1orf37-dup, was identified as a young gene specific to humans. It was derived from the conserved c1orf37 gene through retroposition after the divergence of human and chimpanzee. This gene has evolved rapidly driven by positive Darwinian selection as evident from a significantly high ratio of non-synonymous substitution rate to synonymous substitution rate (K(a)/K(s)=2.08) between the new c1orf37-dup and the parental c1orf37 genes. Population genetics analysis disclosed a very low level of polymorphism in the c1orf37-dup gene and its neighboring regions, thus providing support for the occurrence of a recent selective sweep. The GFP experiments revealed that it encodes a transmembrane protein associated with cell membranes. Non-random distribution of amino acid changes indicates the C1ORF37-DUP protein may have evolved diverged functions in the presumably functionally important N-terminal region in the cytoplasm and the extracellular loop. These lines of evidence support that the functional adaptation of c1orf37-dup has occurred in humans. Unlike its ubiquitously expressed parental gene, c1orf37-dup expresses selectively in several human tissues including brain. It is suggested that c1orf37-dup encodes a novel transmembrane protein in humans which potentially endows new properties to cell surface interactions.

Animals↗

PubMed2006

The testis-specific apoptosis related gene TTL.6 underwent adaptive evolution in the lineage leading to humans.

The TTL.6 gene is a member of the tubulin-tyrosine ligase (TTL) family involved in apoptosis and preferentially expressed in the testis. We sequenced the coding region and part of the introns of TTL.6 in world wide human populations and five representative nonhuman primate species covering great apes, lesser ape and Old World monkey. The sequence substitution patterns of TTL.6 in primates demonstrated a sharp difference in evolutionary rates among different primate lineages. Our results indicated an accelerated evolution of TTL.6 in the human lineage, which was caused by Darwinian positive selection. Further analysis on sequence variations in human populations demonstrated an excess of derived common alleles, which was likely caused by genetic hitchhiking, an implication of recent positive selection on TTL.6 in human populations.

Alleles↗

PubMed2006

Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1.

Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, skeletal myocyte differentiation, and cardiac hypertrophy. We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes through phosphorylation of modulatory calcineurin-interacting protein 1 (MCIP1). However, the protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism of MCIP1-mediated calcineurin regulation have not been defined. Here, we show that MEK5 and big MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin activity through phosphorylation of MCIP1. Genetic studies showed that BMK1-deficient mouse lung fibroblasts failed to mediate MCIP1 phosphorylation and activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring BMK1 to the deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. Thus, using BMK1-deficient mouse lung fibroblast cells, we provided the genetic evidence that BMK1 is required for angiotensin II-mediated calcineurin/NFAT activation through MICP1 phosphorylation. Finally, we discovered that phosphorylated MCIP1 dissociates from calcineurin and binds with 14-3-3, thereby relieving its inhibitory effect on calcineurin activity. In summary, our findings reveal a previously unrecognized essential regulatory role of mitogen-activated protein kinase signaling in calcineurin activation through the reversible phosphorylation of a calcineurin-interacting protein, MCIP1.

14-3-3 Proteins↗

PubMed2006

[Genioplasty with morselized autologous bone graft].

OBJECTIVE: To investigate a new method of genioplasty for treatment of a prominent mandibular angle with mandibular malformation. METHODS: According to the different types of the mandible, the prominent mandibular angle was grinded with the masseter muscle kept intact. Autologous micromorselized bone of the grinded mandibular angle was collected and implanted into the chin for augmentation mentoplasty, and the chin was fixed with gypsum after operation. RESULTS: Fifteen patients receiving the surgery were followed up for 6 -12 months, and satisfactory effects were achieved in 12 patients. One patient requested modification of the shape of the chin 10 days after the operation, and another two sustained chin distortion due to external forces and underwent subsequent shape adjustment of the chin. CONCLUSION: The procedure described avoids graft rejection and causes less complications for genioplasty with easy moulding and satisfactory outcome.

Adolescent↗

PubMed2005

Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways.

Members of the mitogen-activated protein kinase kinase kinase (MAP3K) family are crucial for the Toll-like receptor (TLR) signaling and cellular stress responses. However, the molecular mechanisms underlying the TLR- and cellular stress-mediated MAP3K activation remain largely unknown. In this study, we identified a key regulatory phosphorylation site, serine 519 and serine 526, in MAP3K MEKK2 and MEKK3, respectively. Mutation of this serine to an alanine severely impaired MEKK2/3 activation. We generated an anti-p-MEKK2/3 antibody and used this antibody to demonstrate that lipopolysaccharide induced MEKK2 and MEKK3 phosphorylation on their regulatory serine. We found that the serine phosphorylation was crucial for TLR-induced interleukin 6 production and this process is regulated by TRAF6, a key adaptor molecule for the TLR pathway. We further demonstrated that many, but not all, MAPK agonists induced the regulatory serine phosphorylation, suggesting an involvement of different MAP3Ks in activation of the MAPK cascades leading to different cellular responses. In conclusion, this study reveals a novel molecular mechanism for MEKK2/3 activation by the TLR and cellular stress pathways.

Amino Acid Sequence↗

PubMed2005

TAK1 is recruited to the tumor necrosis factor-alpha (TNF-alpha) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-kappaB activation.

Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-alpha (TNF-alpha)-induced IkappaB kinase (IKK) activation and subsequent activation of transcription factor NF-kappaB. However, the molecular mechanism by which RIP mediates TNF-alpha-induced NF-kappaB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-alpha receptor complex in a RIP-dependent manner following the stimulation of TNF-alpha receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-alpha-induced NF-kappaB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling.

Blotting, Western↗