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At least 757 records · Page 42Linked to original sources
PubMed2000

SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.

During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr(985) does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr(985), suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3.

Carrier Proteins↗
PubMed2001

Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway.

Cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis, is feedback-inhibited at the transcriptional level by hydrophobic bile acids. Recent studies show that bile acids are physiological ligands for farnesoid X receptor (FXR). Activated FXR indirectly represses CYP7A1 transcription through induction of small heterodimer protein (SHP-1). In this study, we provide evidence that bile acids rapidly down-regulate CYP7A1 transcription via activation of the JNK/c-Jun pathway. Furthermore, we demonstrate that SHP-1 is also a direct target of activated c-Jun. In primary rat hepatocyte cultures, taurocholate (TCA) strongly activated JNK in a time- and concentration-dependent manner. Tumor necrosis factor-alpha, a potent activator of JNK, also rapidly activated JNK and down-regulated CYP7A1 mRNA levels. Overexpression of dominant-negative JNK1 or a transactivating domain mutant of c-Jun significantly blocked the ability of TCA to down-regulate CYP7A1 mRNA. In contrast, overexpression of wild-type c-Jun (c-Jun(wt)) enhanced the repression of CYP7A1 by TCA. Moreover, overexpression of c-Jun(wt) resulted in increased SHP-1 promoter activity. Mutation of a putative AP-1 (c-Jun) element suppressed c-Jun-mediated activation of the SHP-1 promoter construct. These results indicate that the bile acid-activated JNK pathway plays a pivotal role in regulating CYP7A1 levels in primary rat hepatocytes.

Animals↗
PubMed2002

Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors.

The X-linked lymphoproliferative (XLP) syndrome gene encodes a protein named SAP or SH2D1A that is composed of a single Src homology 2 (SH2) domain. Two models have been proposed for its function in lymphocyte signaling. One postulates that it acts as an inhibitor of interactions between the phosphatase SHP-2 and the immune receptor SLAM. The other suggests that it functions as an adaptor to promote the recruitment of a kinase, FynT, to SLAM. Here, we provide evidence in support of both roles for SAP. Using an array of peptides derived from the SLAM family of receptors, we demonstrate that SAP binds with comparable affinities to the same sites in these receptors as do the SH2 domains of SHP-2 and SHIP, suggesting that these three proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicate that SAP is capable of binding directly to FynT, an interaction mediated by the FynT SH3 domain. In cells, FynT was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was drastically enhanced by SAP. Because SAP also blocked the recruitment of SHP-2 to SLAM in these cells, we propose a dual functional role for SAP in SLAM signaling by acting both as an adaptor for FynT and an inhibitor to SHP-2 binding. The physiological relevance of the dual functional role for SAP is underscored by the observation that disease-causing SAP mutants exhibited significantly reduced affinities to both FynT and SLAM.

Amino Acid Sequence↗
PubMedDate not supplied

Assignment and serotyping of Trichosporon species: the causative agents of summer-type hypersensitivity pneumonitis.

We re-valued three antigenic types within the genus Trichosporon as the causative agents of summer-type hypersensitivity pneumonitis (SHP). Corresponding standard strains, TIMM 1573 (serotype I), TIMM 1318 (serotype II), and M9456 (serotype III) were assigned to species T. mucoides, T. asahii and T. montevideense, respectively, based on 95% or more DNA/DNA relatedness with each type of culture and other genetical, physiological and morphological characteristics. To confirm the significance of these serotypes, 98 other strains of Trichosporon isolated from patients' environments and 24 CBS strains, including type cultures of species described within the genus, were serotyped. Serum antibody analysis of 220 SHP patients against Trichosporon spp. were also examined to estimate the antigenic profile of SHP. The present results indicate that T. asahii and T. mucoides, which are the most common causes of trichosporonosis, appear to be the major causative agents of SHP. These observations suggest a common pathogenesis of Trichosporon inducing hypersensitivity and infection, depending on the immunological status of the host.

Air Microbiology↗
PubMed2002

Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule?

Fluid shear stress (FSS) induces many forms of responses, including phosphorylation of extracellular signal-regulated kinase (ERK) in endothelial cells (ECs). We have earlier reported rapid tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1) in ECs exposed to FSS. Osmotic changes also induced similar PECAM-1 and ERK phosphorylation with nearly identical kinetics. Because both FSS and osmotic changes should mechanically perturb the cell membrane, they might activate the same mechanosignaling cascade. When PECAM-1 is tyrosine phosphorylated by FSS or osmotic changes, SHP-2 binds to it. Here we show that ERK phosphorylation by FSS or osmotic changes depends on PECAM-1 tyrosine phosphorylation, SHP-2 binding to phospho-PECAM-1, and SHP-2 phosphatase activity. In ECs under flow, detectable amounts of SHP-2 and Gab1 translocated from the cytoplasm to the EC junction. When magnetic beads coated with antibodies against the extracellular domain of PECAM-1 were attached to ECs and tugged by magnetic force for 10 min, PECAM-1 associated with the beads was tyrosine phosphorylated. ERK was also phosphorylated in these cells. Binding of the beads by itself or pulling on the cell surface using poly-l-coated beads did not induce phosphorylation of PECAM-1 and ERK. These results suggest that PECAM-1 is a mechanotransduction molecule.

Animals↗
PubMed1997

The motheaten mutation rescues B cell signaling and development in CD45-deficient mice.

The cytosolic SHP-1 and transmembrane CD45 protein tyrosine phosphatases (PTP) play critical roles in regulating signal transduction via the B cell antigen receptor (BCR). These PTPs differ, however, in their effects on BCR function. For example, BCR-mediated mitogenesis is essentially ablated in mice lacking CD45 (CD45(-)), but is enhanced in SHP-1-deficient motheaten (me) and viable motheaten (mev) mice. To determine whether these PTPs act independently or coordinately in modulating the physiologic outcome of BCR engagement, we assessed B cell development and signaling in CD45-deficient mev (CD45-/SHP-1-) mice. Here we report that the CD45-/SHP-1-) cells undergo appropriate induction of protein kinase activity, mitogen-activated protein kinase activation, and proliferative responses after BCR aggregation. However, BCR-elicited increases in the tyrosine phosphorylation of several SHP-1-associated phosphoproteins, including CD19, were substantially enhanced in CD45-/SHP-1-, compared to wild-type and CD45- cells. In addition, we observed that the patterns of cell surface expression of mu, delta, and CD5, which distinguish the PTP-deficient from normal mice, are largely restored to normal levels in the double mutant animals. These findings indicate a critical role for the balance of SHP-1 and CD45 activities in determining the outcome of BCR stimulation and suggest that these PTPs act in a coordinate fashion to couple antigen receptor engagement to B cell activation and maturation.

Animals↗
PubMed2005

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Germline mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome (NS) and the clinically related LEOPARD syndrome (LS), whereas somatic mutations in the same gene contribute to leukemogenesis. On the basis of our previously gathered genetic and biochemical data, we proposed a model that splits NS- and leukemia-associated PTPN11 mutations into two major classes of activating lesions with differential perturbing effects on development and hematopoiesis. To test this model, we investigated further the diversity of germline and somatic PTPN11 mutations, delineated the association of those mutations with disease, characterized biochemically a panel of mutant SHP-2 proteins recurring in NS, LS, and leukemia, and performed molecular dynamics simulations to determine the structural effects of selected mutations. Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones. Furthermore, we show that the recurrent LS-causing Y279C and T468M amino acid substitutions engender loss of SHP-2 catalytic activity, identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.

Adult↗
PubMed2003

Role of the CD47-SHPS-1 system in regulation of cell migration.

SHPS-1 is a transmembrane protein whose extracellular region interacts with CD47 and whose cytoplasmic region undergoes tyrosine phosphorylation and there by binds the protein tyrosine phosphatase SHP-2. Formation of this complex is implicated in regulation of cell migration by an unknown mechanism. A CD47-Fc fusion protein or antibodies to SHPS-1 inhibited migration of human melanoma cells or of CHO cells overexpressing SHPS-1. Overexpression of wild-type SHPS-1 promoted CHO cell migration, whereas expression of the SHPS-1-4F mutant, which lacks the phosphorylation sites required for SHP-2 binding, had no effect. Antibodies to SHPS-1 failed to inhibit migration of CHO cells expressing SHPS-1-4F. SHPS-1 ligands induced the dephosphorylation of SHPS-1 and dissociation of SHP-2. Antibodies to SHPS-1 also enhanced Rho activity and induced both formation of stress fibers and adoption of a less polarized morphology in melanoma cells. Our results suggest that engagement of SHPS-1 by CD47 prevents the positive regulation of cell migration by this protein. The CD47- SHPS-1 system and SHP-2 might thus contribute to the inhibition of cell migration by cell-cell contact.

Animals↗
PubMed2003

Double-phase parathyroid 99mTc-Sestamibi scintigraphy in chronic haemodialysis patients: correlation with biochemical markers of parathyroid function.

99mTc-Sestamibi identifies the presence of hyperfunctioning autonomous parathyroid glands in patients with secondary hyperparathyroidism (SHP). The objectives of this study were: (i) to evaluate the interdependence between biochemical markers of SHP and 99mTc-Sestamibi uptake; and (ii) to determine whether 99mTc-Sestamibi uptake could be efficiently predicted by any combination of the former variables. Double-phase parathyroid 99mTc-Sestamibi uptake and total serum calcium, phosphorus, intact parathormone, 25-OH vitamin D and 1,25(OH) vitamin D determinations were performed simultaneously in 74 patients (36 female, 38 male) with SHP. Planar images of the neck and upper thorax were obtained in anterior view, 15 min (early phase) and 120 min (delayed phase) after the injection of 740 MBq of 99mTc-Sestamibi. In each patient, a final parathyroid/thyroid (P/T) activity index was obtained by adding the results of the P/T index of all parathyroid lesions. There was a significant correlation between intact parathormone levels and delayed 99mTc-Sestamibi uptake ( r=0.656; P<0.01). Of all the variables, intact parathormone was the only significant predictor of delayed 99Tc-Sestamibi uptake ( r=0.487; P<0.001). Calcium, phosphorus, vitamin D metabolites, age, gender, time spent on haemodialysis and cause of chronic renal failure displayed no significant correlation with 99mTc-Sestamibi uptake. It can be concluded that 99mTc-Sestamibi uptake is a potential predictor of parathyroid function in SHP patients. Hence, 99mTc-Sestamibi scintigraphy could be useful to assess parathyroid function and in the clinical follow-up of these patients.

Age Factors↗
PubMed2004

Schönlein-Henoch purpura during pregnancy: Case report and review of the literature.

The clinical features of Schönlein-Henoch Purpura (SHP) consist of non-thrombocytopenic purpura in association with joint, gastrointestinal and renal involvements. Because it is uncommon in adults, there is little information on the effects of SHP on pregnancy in the literature. This report documents the clinical findings and outcome of an uncommon case of SHP affecting a woman who was 25 weeks pregnant. Prompt steroid-therapy induced a rapidly favorable course and successful vaginal delivery at 40 weeks gestation. If SHP develops during pregnancy, it is not always easy to distinguish from obstetrical complications such as pre-eclampsia. An early diagnosis is important especially if renal involvement exists, because the prognosis for this disease can include nephropathy and it therefore needs close monitoring.

Adult↗
PubMed1989

Concurrent poststreptococcal acute glomerulonephritis and Schönlein-Henoch purpura.

A 5-year-old Japanese boy developed concurrent poststreptococcal acute glomerulonephritis (PSAGN) and Schönlein-Henoch purpura (SHP). An elevated titer of ASK on admission confirmed the preceding streptococcal infection. Arthritis of the left knee and petechiae on admission were regarded as features of SHP. The presence of SHP was further confirmed by the pathological finding of leukocytoclastic vasculitis in the skin. PSAGN was strongly suspected due to the findings of microscopic hematuria and hypocomplementemia in the acute phase. The concurrence of SHP and PSAGN suggests similar underlying pathophysiological processes as poststreptococcal sequelae. At the height of the illness, peripheral blood lymphocyte subset analysis showed a marked increase in the suppressor inducer T subset and a reciprocal decrease in the helper T subset. This alteration in T lymphocyte subsets was regarded as indicative of the immunological derangement in this patient.

Child, Preschool↗
PubMed1992

Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences.

Protein tyrosine phosphatases (PTPases) are a family of enzymes important in cellular regulation. Characterization of two cDNAs encoding intracellular PTPases expressed primarily in hematopoietic tissues and cell lines has revealed proteins that are potential regulators of signal transduction. One of these, SHP (Src homology region 2 [SH2]-domain phosphatase), possesses two tandem SH2 domains at the amino terminus of the molecule. SH2 domains have previously been described in proteins implicated in signal transduction, and SHP may be one of a family of nonreceptor PTPases that can act as direct antagonists to the nonreceptor protein tyrosine kinases. The SH2 domains of SHP preferentially bind a 15,000-Mr protein expressed by LSTRA cells. LSTRA cells were shown to express SHP protein by immunoprecipitation, thus demonstrating a potential physiological interaction. The other PTPase, PEP (proline-, glutamic acid-, serine-, and threonine-rich [PEST]-domain phosphatase), is distinguished by virtue of a large carboxy-terminal domain of approximately 500 amino acids that is rich in PEST residues. PEST sequences are found in proteins that are rapidly degraded. Both proteins have been expressed by in vitro transcription and translation and in bacterial expression systems, and both have been demonstrated to have PTPase activity. These two additional members of the PTPase family accentuate the variety of PTPase structures and indicate the potential diversity of function for intracellular tyrosine phosphatases.

Amino Acid Sequence↗
PubMed1998

Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase.

Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-alpha), and IFN-gamma. Upon the stimulation of IL-6 or IL-3, Gab1 was found to form a complex with phosphatidylinositol (PI)-3 kinase and SHP-2, a homolog of Corkscrew. Mutational analysis of gp130, the common subunit of IL-6 family cytokine receptors, revealed that neither tyrosine residues of gp130 nor its carboxy terminus was required for tyrosine phosphorylation of Gab1. Expression of Gab1 enhanced gp130-dependent mitogen-activated protein (MAP) kinase ERK2 activation. A mutation of tyrosine 759, the SHP-2 binding site of gp130, abrogated the interactions of Gab1 with SHP-2 and PI-3 kinase as well as ERK2 activation. Furthermore, ERK2 activation was inhibited by a dominant negative p85 PI-3 kinase, wortmannin, or a dominant negative Ras. These observations suggest that Gab1 acts as an adapter molecule in transmitting signals to ERK MAP kinase for the cytokine receptor gp130 and that SHP-2, PI-3 kinase, and Ras are involved in Gab1-mediated ERK activation.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Signal regulatory protein alpha ligation induces macrophage nitric oxide production through JAK/STAT- and phosphatidylinositol 3-kinase/Rac1/NAPDH oxidase/H2O2-dependent pathways.

Signal regulatory protein alpha (SIRPalpha) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2. In macrophages SIRPalpha can negatively regulate the phagocytosis of host cells and the production of tumor necrosis factor alpha. Here we provide evidence that SIRPalpha can also stimulate macrophage activities, in particular the production of nitric oxide (NO) and reactive oxygen species. Ligation of SIRPalpha by antibodies or soluble CD47 triggers inducible nitric oxide synthase expression and production of NO. This was not caused by blocking negative-regulatory SIRPalpha-CD47 interactions. SIRPalpha-induced NO production was prevented by inhibition of the tyrosine kinase JAK2. JAK2 was found to associate with SIRPalpha in macrophages, particularly after SIRPalpha ligation, and SIRPalpha stimulation resulted in JAK2 and STAT1 tyrosine phosphorylation. Furthermore, SIRPalpha-induced NO production required the generation of hydrogen peroxide (H(2)O(2)) by a NADPH oxidase (NOX) and the phosphatidylinositol 3-kinase (PI3-K)-dependent activation of Rac1, an intrinsic NOX component. Finally, SIRPalpha ligation promoted SHP-1 and SHP-2 recruitment, which was both JAK2 and PI3-K dependent. These findings demonstrate that SIRPalpha ligation induces macrophage NO production through the cooperative action of JAK/STAT and PI3-K/Rac1/NOX/H(2)O(2) signaling pathways. Therefore, we propose that SIRPalpha is able to function as an activating receptor.

Animals↗
PubMed2004

Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM-1 in PECAM-1-dependent cell migration.

Platelet endothelial cell adhesion molecule (PECAM-1), a transmembrane glycoprotein, has been implicated in angiogenesis, with recent evidence indicating the involvement of PECAM-1 in endothelial cell motility. The cytoplasmic domain of PECAM-1 contains two tyrosine residues, Y663 and Y686, that each fall within an immunoreceptor tyrosine-based inhibitory motif (ITIM). When phosphorylated, these residues together mediate the binding of the protein tyrosine phosphatase SHP-2. Because SHP-2 has been shown to be involved in the turnover of focal adhesions, a phenomenon required for efficient cell motility, the association of this phosphatase with PECAM-1 via its ITIMs may represent a mechanism by which PECAM-1 might facilitate cell migration. Studies were therefore done with cell transfectants expressing wild-type PECAM or mutant PECAM-1 in which residues Y663 and Y686 were mutated. These mutations eliminated PECAM-1 tyrosine phosphorylation and the association of PECAM-1 with SHP-2 but did not impair the ability of the molecule to localize at intercellular junctions or to bind homophilically. However, in vitro cell motility and tube formation stimulated by the expression of wild-type PECAM-1 were abrogated by the mutation of these tyrosine residues. Importantly, during wound-induced migration, the number of focal adhesions as well as the level of tyrosine phosphorylated paxillin detected in cells expressing wild-type PECAM-1 were markedly reduced compared with control cells or transfectants with mutant PECAM-1. These data suggest that, in vivo, the binding of SHP-2 to PECAM-1, via PECAM-1's ITIM domains, promotes the turnover of focal adhesions and, hence, endothelial cell motility.

Amino Acid Motifs↗
PubMed1986

Life span studies in Zaprionus paravittiger with sodium hypophosphite feeding.

The median and maximum life spans of Zaprionus paravittiger at 26 +/- 2 degrees C were 35.45 +/- 0.39 and 70.0 +/- 1.00 days, respectively, in males and 39.93 +/- 0.40 and 77.67 +/- 0.58 days in females. Feeding of an antioxidant-sodium hypophoshite (SHP), 1, 10 1 X 10(2) and 1 X 10(3) microM-resulted in increased survival of both sexes. Further increase in SHP concentration accelerated the mortality rate. Secondly, the lipid peroxide level as measured by malondialdehyde content showed an age-related increase in normal as well as SHP-fed cohorts. However, the rate of increase was much slower in the latter. It is suggested that SHP, by virtue of its free-radical scavenging property, prolongs the life span of Z. paravittiger.

Aging↗
PubMed2003

Integrin-associated protein binding domain of thrombospondin-1 enhances insulin-like growth factor-I receptor signaling in vascular smooth muscle cells.

Insulin-like growth factor-I (IGF-I) stimulates vascular smooth muscle cell (SMC) proliferation and migration. The response of smooth muscle cells to IGF-I is determined not only by activation of the IGF-I receptor but also by at least three other transmembrane proteins, alphaVbeta3, integrin-associated protein (IAP), and SHPS-1. This regulation seems to be attributable to their ability to regulate the transfer of SHP-2 phosphatase, a key component of IGF-I signaling. Ligand occupancy of SHPS-1 with IAP is required for the recruitment and transfer of SHP-2 and subsequent signaling in response to IGF-I. The extracellular matrix protein thrombospondin-1 stimulates an increase in the cell proliferation response to IGF-I. Because thrombospondin-1 is a ligand for IAP, we wished to determine whether the enhancing effect of thrombospondin-1 was mediated through IAP binding. To examine the effect of thrombospondin-1 binding to IAP, we used a peptide termed 4N1K derived from the IAP binding site of thrombospondin-1. Preincubation with 4N1K increased IGF-I-stimulated mitogen-activated protein kinase activation and DNA synthesis. This enhancement seemed to be attributable to its ability to increase the duration of IGF-I-stimulated receptor and insulin receptor substrate-1 (IRS-1) phosphorylation. Preincubation with 4N1K delayed IGF-I stimulation of SHPS-1 phosphorylation (attributable to an alteration in IAP-SHPS-1 interaction), resulting in a delay in SHP-2 recruitment. This delay in SHP-2 transfer seems to account for the increase in the duration of IGF-I receptor phosphorylation and for enhanced downstream signaling. These observations support the conclusion that thrombospondin-1 and IGF-I seem to function coordinately in stimulating smooth muscle proliferation via the thrombospondin-1 interaction with IAP.

Animals↗
PubMed2004

Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4.

Embryonic stem (ES) cells homozygous for a Shp-2 mutation (Shp-2(Delta46-110)) demonstrate leukemia inhibitory factor (LIF) hypersensitivity and increased LIF-stimulated phosphorylation of signal transducer and activator of transcription (STAT3). We hypothesized that LIF-responsive genes in Shp-2(Delta46-110) cells would represent potential candidates for molecules vital for ES cell self-renewal. Using microarray analysis, we detected 41 genes whose expression was modified by LIF in Shp-2(Delta46-110) ES cells. Induction of 2 significantly up-regulated genes, suppressor of cytokine signaling-3 (SOCS-3) and Kruppel-like factor 4 (Klf4), was verified using Northern blotting. ES cells overexpressing SOCS-3 had an increased capacity to differentiate to hematopoietic progenitors, rather than to self-renew. In contrast, ES cells overexpressing Klf4 had a greater capacity to self-renew based on secondary embryoid body (EB) formation. Klf4-transduced d6 EBs expressed higher levels of Oct-4, consistent with the notion that Klf4 promotes ES cell self-renewal. These findings verify the negative role of SOCS-3 on LIF signaling and provide a novel role for Klf4 in ES cell function.

Animals↗