Biomedical subjects

F C Yang

Publications and source records attributed to F C Yang.

At least 19 recordsLinked to original sources

PubMed2001

Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling.

The circadian clock in the suprachiasmatic nucleus (SCN) is thought to drive daily rhythms of behavior by secreting factors that act locally within the hypothalamus. In a systematic screen, we identified transforming growth factor-alpha (TGF-alpha) as a likely SCN inhibitor of locomotion. TGF-alpha is expressed rhythmically in the SCN, and when infused into the third ventricle it reversibly inhibited locomotor activity and disrupted circadian sleep-wake cycles. These actions are mediated by epidermal growth factor (EGF) receptors on neurons in the hypothalamic subparaventricular zone. Mice with a hypomorphic EGF receptor mutation exhibited excessive daytime locomotor activity and failed to suppress activity when exposed to light. These results implicate EGF receptor signaling in the daily control of locomotor activity, and identify a neural circuit in the hypothalamus that likely mediates the regulation of behavior both by the SCN and the retina.

Animals↗

PubMed2001

Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization.

Critical to homeostasis of blood cell production by hematopoietic stem/progenitor (HSC/P) cells is the regulation of HSC/P retention within the bone marrow microenvironment and migration between the bone marrow and the blood. Key extracellular regulatory elements for this process have been defined (cell-cell adhesion, growth factors, chemokines), but the mechanism by which HSC/P cells reconcile multiple external signals has not been elucidated. Rac and related small GTPases are candidates for this role and were studied in HSC/P deficient in Rac2, a hematopoietic cell-specific family member. Rac2 appears to be critical for HSC/P adhesion both in vitro and in vivo, whereas a compensatory increase in Cdc42 activation regulates HSC/P migration. This genetic analysis provides physiological evidence of cross-talk between GTPase proteins and suggests that a balance of these two GTPases controls HSC/P adhesion and mobilization in vivo.

Animals↗

PubMed2001

Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac.

During mouse embryogenesis, primitive erythropoiesis occurs in blood islands of the yolk sac (YS) on the seventh day of gestation. This study demonstrated for the first time the presence of unique primitive megakaryocytic (Mk) progenitors in the early YS, which disappeared by 13.5 days postcoitum (dpc). When 7.5 dpc YS cells were incubated in the presence of stem cell factor (SCF), interleukin (IL)-3, IL-6, erythropoietin (EPO), thrombopoietin (TPO), and granulocyte colony-stimulating factor in methylcellulose clonal culture, not only erythroid bursts but also megakaryocyte colonies were observed. The megakaryocytes in the colonies matured to proplatelet stages and produced platelets as early as day 3 of culture, much earlier than those from adult bone marrow, although their ploidy class was lower. These megakaryocytes were stained with acetylcholine esterase, and expressed platelet glycoprotein (GP)Ib beta, GPIIIa, and platelet factor 4 by reverse transcription-polymerase chain reaction analysis. The analysis of hemoglobin types in erythrocytes obtained from hematopoietic multilineage colonies containing the megakaryocytes indicated that the Mk progenitors originated from primitive hematopoiesis. The primitive Mk progenitors formed colonies in the absence of any cytokines in fetal bovine serum (FBS)-containing culture, and SCF, IL-3, EPO, and TPO significantly enhanced the Mk colony formation. In FBS-free culture, however, no colony formation was induced without these cytokines. Because megakaryocytes were detected in 8.5-dpc YS, these unique primitive Mk progenitors may rapidly mature and give rise to platelets to prevent hemorrhage in the simultaneously developing blood vessels until definitive hematopoiesis begins to produce platelets. (Blood. 2001;97:2016-2022)

Animals↗

PubMed2001

Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency.

The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells. Genetic targeting studies in mice showed that Rac2 is an essential regulator of neutrophil chemotaxis, L-selectin capture and rolling, and superoxide production. Recently, a dominant negative mutation of Rac2, D57N, has been reported to be associated with a human phagocytic immunodeficiency. To understand further the cellular phenotypes associated with this D57N Rac2 mutant we examined its biochemical characteristics and functional effects when expressed in primary murine bone marrow cells. When compared with wild type (WT) Rac2, D57N Rac2 displayed approximately 10% GTP binding ability resulting from a markedly enhanced rate of GTP dissociation and did not respond to the guanine nucleotide exchange factors. These results suggest that D57N Rac2 may act in a dominant negative fashion in cells by sequestering endogenous guanine nucleotide exchange factors. When expressed in hematopoietic cells, D57N Rac2 reduced endogenous activities of not only Rac2, but also Rac1 and decreased cell expansion in vitro in the presence of growth factors due to increased cell apoptosis. Unexpectedly, D57N expression had no effect on proliferation. In contrast, expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation. Transplantation of transduced bone marrow cells into lethally irradiated recipients showed that the percentage of D57N-containing peripheral blood cells decreased markedly from 40% at 1 month to <5% by 3 months postinjection. Neutrophils derived in vitro from the transduced progenitor cells containing D57N demonstrated markedly impaired migration and O(2)(-) responses to formyl-methionyl-leucyl-phenylalanine, reflecting the same cellular phenotype in these differentiated cells as those described previously in patient cells. These data suggest that the phenotypic abnormalities associated with D57N Rac2 may involve not only neutrophil cellular functions, but also abnormal cell survival in other hematopoietic cells and that overexpression of Rac leads to increased proliferation of normal cells in vitro, whereas deficiency of Rac leads to increased apoptosis.

Amino Acid Substitution↗

PubMed2001

Genetic dissection of melanoma pathways in the mouse.

The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a)and p19(ARF)in human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mouse have shown that activated RAS mutation can cooperate with INK4a(Delta 2/3)deficiency (null for both p16(INK4a)and p19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functional link between p19(ARF)and p53, we have now shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse. Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

Animals↗

PubMed2000

An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90.

Members of the postsynaptic density-95 (PSD-95)/SAP90 family of membrane-associated guanylate kinase (MAGUK) proteins function as multimodular scaffolds that organize protein-signaling complexes at neuronal synapses. MAGUK proteins contain PDZ, Src homology 3 (SH3), and guanylate kinase (GK)-like domains, all of which can function as sites for specific protein-protein interactions. We report here a direct protein-protein interaction between the SH3 domain and the GK region in the PSD-95 family of MAGUKs. The SH3 domain of the PSD-95 family appears to have an atypical binding specificity, because the classical SH3 binding (-P-X-X-P-) motif is absent from the GK domain. Although SH3-GK binding can occur in either an intramolecular or intermolecular manner, the intramolecular mode is preferred, possibly because of additional tertiary interactions available when the SH3 and GK domains are adjacent in the same polypeptide. Mutations disrupting the intramolecular SH3-GK interaction do not interfere with PSD-95 association with the K(+) channel Kv1.4 or with the GK domain-binding protein GKAP. The same mutations, however, inhibit the clustering of Kv1.4 by PSD-95, suggesting that the intramolecular SH3-GK interaction may modulate the clustering activity of PSD-95.

Animals↗

PubMed2000

Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.

Membrane-associated guanylate kinases (MAGUKs) contain multiple protein-binding domains that allow them to assemble specific multiprotein complexes in particular regions of the cell. CASK/LIN-2, a MAGUK required for EGF receptor localization and signalling in Caenorhabditis elegans, contains a calmodulin-dependent protein kinase-like domain followed by PDZ, SH3 and guanylate kinase-like domains. In adult rat brain, CASK is concentrated at neuronal synapses and binds to the cell-surface proteins neurexin and syndecan and the cytoplasmic proteins Mint/LIN-10 and Veli/LIN-7. Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. Our findings show that a MAGUK which is usually associated with cell junctions has a transcription regulation function.

Animals↗

PubMed2000

Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo.

Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W(41) mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras-mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W(41)) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

Animals↗

PubMed2000

Neural transplants. effects On startle responses in neonatally MSG-treated rats.

Neonatal monosodium glutamate (MSG) treatment has been associated with dysfunctions in stress responses. Therefore, the present study aimed at examining the acoustic startle response (ASR) in MSG-treated rats and the effects of fetal neural transplantation. Male and female rats were given MSG (4 mg/g) or saline on alternate days from days 2-10 after birth. To determine whether fetal transplants could reverse behavioral impairments observed in MSG-treated rats, at 12 days of age MSG-treated rats received either arcuate nucleus (AN), cortical fetal grafts, or sham surgery into the third ventricle. ASR amplitude was measured at 35-40 days of age, and again in adulthood. MSG produced the expected decrease in the density of hypothalamic neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the AN area. Corticotropin-releasing factor (CRF) neurons/fibers were not affected by MSG. Pituitary atrophy was observed in all MSG rats. We report a permanent increase in the amplitude and reduction in short-term habituation of ASR in all MSG-treated rats. No effect was observed on long-term habituation in male rats. Cortical, but not AN tissue significantly reduced the magnitude of ASR in MSG animals. The results are discussed in terms of the central pathways mediating ASR, in particular hypothalamo-amygdala connections. It is considered that nonspecific factors mediate recovery produced by cortical tissue grafts, as observed in other models of neural transplantation.

Animals↗

PubMed2000

Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells.

Mast cells generated from Rac2-deficient (-/-) mice demonstrated defective actin-based functions, including adhesion, migration, and degranulation. Rac2(-/-) mast cells generated lower numbers and less mast cell colonies in response to growth factors and were deficient in vivo. Rac2(-/-) mast cells demonstrated a significant reduction in growth factor-induced survival, which correlated with the lack of activation of Akt and significant changes in the expression of the Bcl-2 family members BAD and Bcl-XL, in spite of a 3-fold induction of Rac1 protein. These results suggest that Rac2 plays a unique role in multiple cellular functions and describe an essential role for Rac2 in growth factor-dependent survival and expression of BAD/Bcl-XL.

Actins↗

PubMed1999

Differential effects of human granulocyte colony-stimulating factor (hG-CSF) and thrombopoietin on megakaryopoiesis and platelet function in hG-CSF receptor-transgenic mice.

Granulocyte-colony stimulating factor (G-CSF) has been found to act on the neutrophilic lineage. We recently showed that human G-CSF (hG-CSF) has effects similar to early-acting cytokines such as interleukin-3 (IL-3) in the development of multipotential hematopoietic progenitors in transgenic (Tg) mice expressing receptors (R) for hG-CSF. In the present study, we examined the effects of hG-CSF on more mature hematopoietic cells committed to megakaryocytic lineage in these Tg mice. The administration of hG-CSF to the Tg mice increased the numbers of both platelets in peripheral blood and megakaryocytes in the spleen, indicating that hG-CSF stimulates megakaryopoiesis in the Tg mice in vivo. The stimulatory effect of hG-CSF was also supported by the results of studies in vitro. hG-CSF supported megakaryocyte colony formation in a dose-dependent fashion in clonal cultures of bone marrow cells derived from the Tg mice. Direct effects of hG-CSF on megakaryocytic progenitors in the Tg mice were confirmed by culture of single-cell sorted from bone marrow cells. hG-CSF showed a stronger effect on maturation of megakaryocytes in the Tg mice than that of IL-3 alone, but weaker than that of TPO alone. In addition, hG-CSF induced phosphorylation of STAT3 but not Jak2 or STAT5, while TPO induced phosphorylation of both. In contrast to TPO, hG-CSF did not enhance ADP-induced aggregation. Thus, hG-CSF has a wide variety of functions in megakaryopoiesis of hG-CSFR-Tg mice, as compared with other megakaryopoietic cytokines, but the activity of hG-CSF in megakaryocytes and platelets does not stand up to a comparison with that of TPO. Specific signals may be required for the full maturation and activation of platelets.

Animals↗

PubMed1999

Synthesis and evaluation of backbone/amide-modified analogs of leualacin.

Leualacin (1), a cyclic depsi-pentapeptide, and its backbone/amide-modified analogs 2-4 were synthesized. Amide analogue 3 exhibited stronger vasodilatory effects. It also strongly inhibited collagen- and arachidonic acid (AA)-induced platelet aggregations with IC50s of 0.6 microM and 2.0 microM, respectively.

Animals↗

PubMed1998

Human granulocyte colony-stimulating factor (G-CSF) stimulates the in vitro and in vivo development but not commitment of primitive multipotential progenitors from transgenic mice expressing the human G-CSF receptor.

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation and restricted differentiation of hematopoietic progenitors into neutrophils. To clarify the effects of G-CSF on hematopoietic progenitors, we generated transgenic (Tg) mice that had ubiquitous expression of the human G-CSF receptor (hG-CSFR). In clonal cultures of bone marrow and spleen cells obtained from these mice, hG-CSF supported the growth of myelocytic as well as megakaryocytic, mast cell, mixed, and blast cell colonies. Single-cell cultures of lineage-negative (Lin-)c-Kit+Sca-1(+) or Sca-1(-) cells obtained from the Tg mice confirmed the direct effects of hG-CSF on the proliferation and differentiation of various progenitors. hG-CSF also had stimulatory effects on the formation of blast cell colonies in cultures using 5-fluorouracil-resistant hematopoietic progenitors and clone-sorted Lin-c-Kit+Sca-1(+) primitive hematopoietic cells. These colonies contained different progenitors in proportions similar to those obtained when mouse interleukin-3 was used in place of hG-CSF. Administration of hG-CSF to Tg mice led to significant increases in spleen colony-forming and mixed/blast cell colony-forming cells in bone marrow and spleen, but did not alter the proportion of myeloid progenitors in total clonogenic cells. These results show that, when functional G-CSFR is present on the cell surface, hG-CSF stimulates the development of primitive multipotential progenitors both in vitro and in vivo, but does not induce exclusive commitment to the myeloid lineage.

Animals↗

PubMed1998

Stimulation of mouse and human primitive hematopoiesis by murine embryonic aorta-gonad-mesonephros-derived stromal cell lines.

We report here on a novel stromal cell line, AGM-S3, derived from the aorta-gonad-mesonephros (AGM) region of a 10.5 days postcoitum (dpc) mouse embryo. The AGM-S3 cells promoted production of hematopoietic progenitors and day-12 spleen colony-forming cells from Lin-c-Kit+Sca-1(+) murine primitive hematopoietic cells. They also supported for 6 weeks generation of human multipotential progenitors from cord blood CD34(+)CD38(-) primitive hematopoietic cells. Human long-term repopulating hematopoietic stem cells (LTR-HSC) with the potential to reconstitute hematopoiesis in NOD/SCID mice were maintained on AGM-S3 cells for at least 4 weeks. Flow cytometric analysis showed that CD13, vascular cellular adhesion molecule-1, and Sca-1 were expressed on AGM-S3 cells. Because stem cell factor, interleukin-6 (IL-6), and oncostatin M, but not IL-3, IL-11, leukemia- inhibitory factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, and Flk2 ligand were detected in reverse transcription-polymerase chain reaction analysis of AGM-S3 cells, the cells seem to express species-cross reactive molecule(s) other than the cytokines examined and which act on primitive hematopoietic progenitor/stem cells. This cell line is expected to elucidate molecular mechanisms regulating early hematopoiesis and pave the way for developing strategies for expansion of human transplantable HSC.

ADP-ribosyl Cyclase↗

PubMed1998

Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses.

CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.

Amino Acid Sequence↗

PubMed1997

Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells.

Leptin, the product of obese gene, was originally identified as a factor regulating body-weight homeostasis and energy balance. The present study has shown that leptin acts on murine hematopoiesis in vitro. In the culture of bone marrow cells (BMC) of normal mice, leptin induced only granulocyte-macrophage (GM) colony formation in a dose-dependent manner, and no other types of colonies were detected even in the presence of erythropoietin (Epo). Leptin also induced GM colony formation from BMC of db/db mutant mice whose leptin receptors were incomplete, but the responsiveness was significantly reduced. The effect of leptin on GM colony formation from BMC of normal mice was also observed in serum-free culture, and comparable with that of GM-colony-stimulating factor (CSF ). Although leptin alone supported few colonies from BMC of 5-fluorouracil (5-FU)-treated mice in serum-free culture, remarkable synergism between leptin and stem cell factor (SCF ) was obtained in the colony formation. The addition of leptin to SCF enhanced the SCF-dependent GM colony formation and induced the generation of a number of multilineage colonies in the presence of Epo. When lineage (Lin)-Sca-1(+) cells sorted from BMC of 5-FU-treated mice were incubated in serum-free culture, leptin synergized with SCF in the formation of blast cell colonies, which efficiently produced secondary colonies including a large proportion of multilineage colonies in the replating experiment. In serum-free cultures of clone-sorted Lin-c-Kit+Sca-1(+) and Lin-c-Kit+Sca-1(-) cells, although synergism of leptin and SCF was observed in the colony formation from both cells, leptin alone induced the colony formation from Lin-c-Kit+Sca-1(-), but not Lin-c-Kit+Sca-1(+) cells. These results have shown that leptin stimulates the proliferation of murine myelocytic progenitor cells and synergizes with SCF in the proliferation of primitive hematopoietic progenitors in vitro.

Animals↗

PubMed1997

Characterization of guanylate kinase-associated protein, a postsynaptic density protein at excitatory synapses that interacts directly with postsynaptic density-95/synapse-associated protein 90.

The structure of central synapses is poorly understood at the molecular level. A recent advance came with the identification of the postsynaptic density-95 (PSD-95)/synapse-associated protein 90 family of proteins as important mediators of the synaptic clustering of certain classes of ion channels. By yeast two-hybrid screening, a novel protein termed guanylate kinase-associated protein (GKAP) has been isolated that binds to the GK-like domain of PSD-95 (). Here we present a detailed characterization of GKAP expression in the rat brain and report the cloning of a novel GKAP splice variant. By Northern blot, GKAP mRNAs (4, 6.5, and 8 kB) are expressed predominantly in the rat brain. By in situ hybridization, GKAP is expressed widely in neurons of cortex and hippocampus and in the Purkinje and granule cells of the cerebellum. On brain immunoblots, two prominent bands of 95 and 130 kDa are detected that correspond to products of short and long N-terminal splice variants of GKAP. Two independent GKAP antibodies label somatodendritic puncta in neocortical and hippocampal neurons in a pattern consistent with synaptic elements. Immunogold electron microscopy reveals GKAP to be predominantly postsynaptic and present at asymmetric synapses and in dendritic spines. The distribution of GKAP immunogold particles is uniform in the lateral plane of the PSD but peaks in the perpendicular axis approximately 20 nm from the postsynaptic membrane. In cultured hippocampal neurons GKAP immunoreactive puncta colocalize with the AMPA receptor subunit Glu receptor 1 but not with the GABAA receptor subunits beta2 and beta3. Thus GKAP is a widely expressed neuronal protein localized specifically in the PSD of glutamatergic synapses, consistent with its direct interaction with PSD-95 family proteins.

Amino Acid Sequence↗

PubMed1997

Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein.

CIITA is a positive regulator of class II major histocompatibility complex gene transcription that has been found to be defective in one of the five complementation groups of class II major histocompatibility complex-negative cell lines. Its N-terminal region is capable of activating transcription from a reporter gene when fused to a DNA binding domain. We have investigated the mechanism of transactivation mediated by the CIITA activation domain by studying its role in the process of transcription initiation and elongation. Specifically the altered specificity TBP (TATA box binding protein) assay has been used to analyze the response of the CIITA activation domain to mutations in TBP known to disrupt its interaction with its associated general factors. Transactivation by CIITA was extremely sensitive to a mutation in TBP that in yeast is known to abolish VP16-mediated transcription but leaves basal transcription unaffected. A TBP mutant defective in interaction with TBP-associated factor TAFII250 also failed to mediate transactivation through the CIITA activation domain. Certain interactions between TBP and general factors that are specifically required for acidic activation domains were also required for CIITA-mediated transactivation to reach its full potential. Finally, like VP16, CIITA was able to stimulate elongation of transcription. Overall the mechanism of transactivation by the human B-cell-specific CIITA is very similar to that mediated by the herpes virus transactivator VP16 in the ways that have been tested.

B-Lymphocytes↗