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Biomedical subjects

L Pan

Publications and source records attributed to L Pan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Evidence for specific annexin I-binding proteins on human monocytes.

Recombinant human annexin I and a monoclonal antibody specific for this protein (mAb 1B) were used to investigate surface binding of this member of the annexin family of proteins to peripheral blood monocytes. Flow cytometric analysis demonstrated trypsin-sensitive, saturable binding of annexin I to human peripheral blood monocytes but not to admixed lymphocytes. A monoclonal antibody that blocks the anti-phospholipase activity of annexin I also blocked its binding to monocytes. These findings suggest the presence of specific binding sites on monocytes. Furthermore, surface iodination, immunoprecipitation and SDS/PAGE analysis were used to identify two annexin I-binding proteins on the surface of monocytes with molecular masses of 15 kDa and 18 kDa respectively. The identification and characterization of these annexin I-binding molecules should help us to better understand the specific interactions of annexin I with monocytes that lead to down-regulation of pro-inflammatory cell functions.

Annexin A1↗
PubMed1996

Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: histology, polymerase chain reaction, or both?

The differential diagnosis between Helicobacter pylori (H pylori-associated chronic gastritis and low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) and the assessment of endoscopic biopsy specimens after treatment of lymphoma can be problematic. Although immunocytochemistry can be used to identify clonal B-cell populations, which are characteristic of MALT lymphoma, its application to small biopsy specimens and the subsequent interpretation can be difficult. The polymerase chain reaction (PCR) can detect clonal B-cell populations by analysis of the Ig heavy chain gene in routinely fixed paraffin-embedded material and might provide a useful tool in the assessment of these specimens. We have investigated the value of histology and PCR in the diagnosis of lymphoma and its followup in formalin-fixed paraffin-embedded gastric endoscopy biopsy specimens from 69 sequential patients selected on the basis of a dense mucosal lymphoid infiltrate associated with H pylori infection. Histologic evidence of MALT lymphoma was identified in 13 cases, 9 of which showed PCR-detected monoclonality. In 12 of 13 cases, H pylori was eradicated, and in 11 of 12 cases, histologic regression of the lymphoma followed. PCR evidence of monoclonality disappeared in 6 of 9 originally monoclonal cases. This was synchronous with histologic remission in 1 case, but lagged in the remaining 5 cases by up to 28 months. Two of the 3 of the 9 cases originally monoclonal by PCR that have not shown molecular regression have monoclonal-amplified products 17 and 24 months after negative histology. In 3 cases, the histology of the biopsies was considered indeterminate or discordant. In 1 of these cases, the histologic features were obscured by crush artefact. In a second case, there was molecular evidence of monoclonality in the absence of histologic features suggestive of lymphoma; this persisted after H pylori eradication. An additional single case originally diagnosed as reactive developed a PCR detectable clonal population 29 months after original evaluation in the absence of histologic features of lymphoma but in the presence of persistent H pylori infection. These findings suggest that the histologic assessment of gastric biopsies remains the method of choice for the diagnosis of lymphoma in gastric endoscopic biopsies with a dense mucosal lymphoid infiltrate. PCR provides a useful technique to support the diagnosis if clonal amplification products are found. The significance of PCR detected clonality in the absence of histologic evidence of lymphoma in uncertain but may represent a stage of tumor progression/regression when the clonal population is insufficient to be detected by conventional histology. This is supported by the evidence that PCR-detectable monoclonality can persist after treatment and the disappearance of histologically detectable lymphoma.

Adolescent↗
PubMed1996

Positive correlation between apoptotic and proliferative indices in gastrointestinal lymphomas of mucosa-associated lymphoid tissue (MALT).

To understand the role of deregulation of apoptosis in the pathogenesis of gastrointestinal MALT lymphoma, apoptosis has been quantitatively studied in paraffin sections from 40 cases (19 low grade, 21 high grade). The extent of apoptosis was correlated with histological grade, proliferative activity as measured by immunostaining of Ki67 proliferation antigen, and the expression of bcl-2 and p53 oncoproteins, which are known to participate in the regulation of apoptosis. Both apoptotic and proliferative indices were significantly (P < 0.00001) higher in high-grade than in low-grade tumours. Overall, apoptotic indices were negatively correlated with bcl-2 expression, particularly in low-grade tumours in which both strong bcl-2 expression and low levels of apoptosis were observed. Thus, the slow expansion of low-grade MALT lymphoma may partly result from a prolonged life-span of tumour cells, due to bcl-2-mediated blockage of apoptosis. No difference in apoptotic indices was found between p53-positive and p53-negative cases. Furthermore, correlation analysis revealed a significantly positive association between apoptotic and proliferative indices. This supports the current belief that the mechanisms controlling apoptosis and proliferation are both activated during the cell cycle and whether a cell enters the proliferation cycle or the apoptotic process depends on survival factors.

Apoptosis↗
PubMed1996

The immunopathophysiology of acute graft-versus-host-disease.

The major complication after allogeneic bone marrow transplantation (BMT) is the development of graft-versus-host-disease (GVHD). This disease is initiated during the conditioning of the recipient, when host tissues are damaged. During the afferent phase of the disease, alloreactive donor T cells recognize foreign major and minor histocompatibility antigens of host tissues. The efferent phase includes activation of inflammatory effector cells as well as the secretion of cytopathic molecules which induce pathology in skin, gastrointestinal tract, liver, lung, and the immune system. Substantial experimental and clinical evidence now indicates a central role of cytokines in the immunopathophysiology of acute GVHD, which forms the basis of this review. The balance between cytokines released by T helper 1 (Th1) cells (interleukin 2, interferon-gamma) or by T helper 2 (Th2) cells (interleukin 4, interleukin 10) after allogeneic BMT is hypothesized to govern the extent of the systemic inflammatory response. Because Th2 cytokines can inhibit the production of proinflammatory cytokines such as interleukin 1 and tumor necrosis factor-alpha, a Th1-->Th2 shift in the initial response of donor T cells may interrupt the cytokine cascade and thus offer a new approach to the prevention and treatment of acute GVHD. Successful interventions to modify the response of donor T cells may obviate the need for T cell depletion and thereby avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.

Acute Disease↗
PubMed1996

Low grade gastric B-cell lymphoma of mucosa associated lymphoid tissue in immunocompromised patients.

An increased incidence of non-Hodgkin's lymphoma is seen in patients with immunodeficiency from any cause. The majority of these are high grade B-cell lymphoma and most are associated with the Epstein-Barr virus (EBV). In post-transplant lymphoma/lymphoproliferative disorders the tumour may regress following reduction of immuno-suppression but in AIDS the lymphomas show a characteristic aggressive course and poor prognosis. We describe low grade B-cell gastric lymphoma of mucosa associated lymphoid tissue (MALT) in three immunocompromised patients (two post-transplant, one HIV positive). In each case, the tumour showed classical morphological features of gastric MALT lymphoma and was not associated with EBV. Helicobacter pylori was identified in each case. Clinical follow-up suggests that the behaviour in these tumours is similar to that seen in MALT lymphomas in immunocompetent patients and not typical of the lymphomas usually associated with immunosuppression. Although the finding of MALT lymphoma in immunosuppressed patients might be coincidental, the association of some MALT lymphomas with autoimmune disease suggests that dysregulation of the immune system might play a role in the pathogenesis of these tumours.

Aged↗
PubMed1996

Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice.

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.

Animals↗
PubMed1996

Stereotactic Gamma thalamotomy for the treatment of parkinsonism.

From September 1994 to June 1995, eight patients with intractable parkinsonism underwent gamma thalamotomy in our hospital. All of these patients were male, with an average age of 59.3 years. The duration of the disease from initial diagnosis was 2-10 years (mean 6.8 years). All had failed or had serious side effects with antiparkinsonian medicine. Seven cases had tremor-dominant symptoms, while the other had mainly rigidity. Six cases had bilateral symptoms. Computed tomography or magnetic resonance imaging (MRI) was undertaken prior to treatment in all cases to exclude focal brain lesions. Stereotactic MRI was taken with the Leksell frame in place and both T1- and T2-weighted images were obtained. The targets were located in the area of Vim/Voa/Vop based on the Schaltenbrand atlas. In seven cases, two plugged 4-mm-collimator shots were used. The maximum dose was 160 Gy in six cases and 180 Gy in one case. In another case, a single 4-mm-collimator shot was used, and a maximum dose of 160 Gy was delivered to the target center. The border of the internal capsule was outside the 20-30% isodose line. We intended the 50% isodose line to have an oval-shaped region with the use of two shots and should correspond to the shape of Vim. Follow-up data were available for six patients (mean: 4.5 months, range: 2-9 months). Tremor disappeared in three cases and improved in the other three. In one of these six cases, the tremor disappeared just 3 days after gamma thalamotomy. Rigidity improved in four of these six cases. In only one patient, treated with a maximum dose of 180 Gy, was there any contralateral limb weakness, which developed 3 months after treatment and has been recovering gradually. Follow-up MRI T2-weighted images in this case showed that the diameter of the lesion was larger than intended and there was a region of diffuse edema in the thalamus and upper brain stem. No other complications occurred in this series.

Adult↗
PubMed1996

Preliminary application of Gamma Knife in the treatment of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is a malignant tumor which occurs frequently in China. Currently, radiotherapy using 60Co is the main method of treatment. However, the 5-year survival rate is only 49.5%. There is no effective method today for treating residual or recurrent tumor following radiotherapy. In principle, the Leksell Gamma Knife could contribute to better results. Since December 1993, we have treated 36 patients suffering from nasopharyngeal carcinoma with the Gamma Knife: 32 were relapses after radiotherapy and 4 were primary cases. Treatment was very effective for a short period. The rate of improvement of such symptoms as headache, facial paralysis, reduced vision, nasal obstruction and nasal bleeding was 70-100%. After treatment, tumors became smaller or even disappeared. A new nasopharyngeal biopsy was performed in 12 patients and demonstrated that the pathological tissue had returned to normal. The short duration of the survey precludes conclusions about the long-term effects of the treatment.

Adult↗
PubMed1996

Replication error phenotype and p53 gene mutation in lymphomas of mucosa-associated lymphoid tissue.

Low grade mucosa-associated lymphoid tissue (MALT) lymphomas commonly arise from a background of chronic inflammatory lesions and can transform into high grade tumors at a late stage. Because chronic inflammation is closely associated with genetic instability, which is one of the mechanisms leading to activation of oncogenes and inactivation of tumor suppressor genes, it is possible that genetic instability plays an important role in MALT lymphomagenesis. In this study, we have examined the frequency of replication error (RER+) phenotype, a newly defined manifestation of genetic instability, and its relationship to p53 mutations in 40 MALT lymphomas (16 high grade and 24 low grade). RER+ phenotype was detected in 21/40 (52.5%) MALT lymphomas (12/24, 50% in low grade; 9/16, 56.2% in high grade). Five of seven reactive lymphoid infiltrates adjacent to tumors also showed one microsatellite alteration, four of which were identified in the corresponding lymphoma lesions in the same patient. In five RER+ high grade lymphomas with low grade lesions, homogeneous and heterogeneous microsatellite alterations were observed between the two components. The same 40 cases were investigated for p53 gene mutations at exons 5 to 8 by PCR-SSCP and direct sequencing. p53 point mutations were found in 11 (27.5%) of the 40 cases. These mutations were statistically related to RER+ phenotype (P < 0.05). Our results demonstrate that the RER+ phenotype is a common genetic feature of MALT lymphomas. Genetic instability occurs throughout the spectrum of the lymphoma development and may be related to the accumulation of genetic aberrations such as p53 mutations. The observation of identical microsatellite alterations between the adjacent lymphoid infiltrates and their corresponding lymphomas provides genetic evidence for evolutionary link of the two lesions. The homogeneous and heterogeneous microsatellite alterations observed between low and high grade components indicate their clonal lineage and genetic diversity.

Base Sequence↗
PubMed1996

Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion.

Indirect antigenic stimulation by H. pylori-specific T cells is implicated in the development of low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT), however, the role of direct antigen stimulation is unknown. To study the role of direct antigen stimulation in MALT lymphomagenesis and its relationship with the pathogenesis of distinct pathological lesions, which represent different stages of the tumour progression, we cloned and sequenced the rearranged immunoglobulin (Ig) heavy chain gene in three low-grade (two from the lung, one from the stomach) and one high-grade (from the stomach) cases. In the low-grade gastric case, we studied the Ig sequence in primary as well as its disseminated and recurrent tumours. In the high-grade gastric case, we analysed the Ig sequence in tumour cell populations microdissected from the residual diffuse low-grade lesions, diffuse high-grade areas from follicles colonized by high-grade blasts. Compared with the published germline sequences, the heavy chain variable (VH) genes of three MALT lymphomas, in which the putative germline was identified, contained frequent somatic mutations, showing a much higher ratio of replacement/silent mutations in the complementarity determining regions (CDRs) than the framework regions (FRs). Ongoing mutation as indicated by intraclonal variation of the Ig sequence clearly existed in low-grade tumour including its dissemination and recurrence, but was not evident in high-grade tumour cell populations including those microdissected from independent colonized follicles. In addition, the germlines of VH genes used by the three MALT lymphomas are frequently found in autoreactive antibodies. Our results suggest that MALT lymphoma derives from postgerminal centre memory B cells, possibly autoreactive B cell clones, and that direct antigen stimulation may play an important role in the clonal expansion of low-grade MALT lymphoma.

Animals↗
PubMed1996

[Cardiotoxicity of 5-fluorouracil].

OBJECTIVE: To determine the possibility and magnitude of cardiotoxicity following high dose intravenous infusion of fluorouracil (5-FU). METHODS: A prospective clinical study was performed on 104 patients with choriocarcinoma and invasive mole. 5-FU was administered by slow intravenous infusion in 5% glucose 500 ml for 8 hours at doses of 28-30 mg.kg-1.day-1 when used as a single agent treatment or 24-26 mg.kg-1.day-1 when used in combination with kengshengmycin (KSM). The total cycles of treatment with 5-FU + KSM were 109 and those of 5-FU or KSM each used as a single agent were 71 and 12 respectively. The cardiac functions were monitored by cardiac symptoms, ECG and serum cardiac enzymes before and after 5-FU infusion. RESULTS: Among the 192 treatment cycles tachycardia, palpitation or cardiac distress were observed in 14 cycles. ECG showed changes of ST or T waves in 8 cycles, sinus tachycardia in 3 cycles. The results of serum cardiac enzyme determinations were variable. The diagnostic criteria of cardiotoxicity were appearances of abnormalities manifested in any two of the three monitor items. The incidence of cardiotoxicity was 4.2% in 5-FU group, 4.6% in 5-FU + KSM group and 0% in KSM group. All episodes were mild, reversible spontaneously after cessation of chemotherapy and did not reappear in subsequent chemotherapeutic cycles. Seven patients with definite cardiac diseases before chemotherapy were given 5-FU treatment, but no obvious aggravation of cardiotoxicities were observed even with repeated 5-FU treatments. CONCLUSION: Only occasional cardiotoxicities were observed in 5-FU treatments. They were rather mild and reversible. The incidence of cardiotoxicity might be reduced with emphasis on strict observance of the treatment regimen in regard to the dosage used, the speed of the infusion and attention to the treatment of any side-effects.

Adult↗
PubMed1996

Long-term engraftment, graft-vs.-host disease, and immunologic reconstitution after experimental transplantation of allogeneic peripheral blood cells from G-CSF-treated donors.

Peripheral blood cells (PBPC) are an alternative source of bone marrow for allogeneic transplantation. Reports from recent clinical trials granulocyte colony-stimulating factor (G-CSF)-mobilized PBPC for allogeneic transplantation show incidence and severity of graft-vs.-host disease (GVHD) similar to those observed in conventional bone marrow transplantation (BMT), despite the presence of 10- to 20-fold more T cell in the PBPC inoculum. In the present study, we examined the effects of pretreatment of donors with G-CSF on GVHD, long-term engraftment, and lymphocyte reconstitution in a murine parent-->F1 model (B6.Ly-5a-->B6d2F1) using splenocytes as a source of peripheral progenitor cells. Recipients of splenocytes from G-CSF-treated donors experienced less mortality from acute GVHD and showed sustained weight gain by day 100 after transplantation. At that time, there was no histological evidence od GVHD in either liver or gut. Recipients of splenocytes from G-CSF-treated donors showed complete donor engraftment within 1 month, which was sustained until the end of the observation period. In contrast, recipients of T cell-depleted splenocytes showed slower donor engraftment and persistent donor/host chimerism. In addition, lymphocyte phenotype and function in mice receiving splenocytes from G-CSF-treated donors was significantly restored by day 100 after transplantation. Thus, the use of G-CSF-mobilized PBPC may provide significant advantages to conventional BMT by reducing GVHD without impairing long-term engraftment and immunologic reconstruction.

Animals↗
PubMed1996

[Study on small intestinal lumenal and membrane flora of 30 healthy Chinese].

Lumenal and membrane flora were investigated using ileum and jejunum samples obtained through endoscopy. 10 kinds of representative anaerobic or aerobic bacteria were cultured for quantitative and qualitative analysis. The result showed there were significant differences between lumenal and membrane flora on Clostridium of ileum, Lactobacillus and Bacillus bifudus in jejunum (P < 0.05). Enterococci were not found in all of these 30 patients. In jenumum, E. Coli was found in 53.3% (16/30) of lumenal flora and 33.3% (10/30) of membrane flora, Bacteroides were found in 40.0% (12/30) of lumenal flora and 33.3% (10/30) of membrane flora respectively.

Adolescent↗
PubMed1995

Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease.

The incidence and severity of acute graft-versus-host disease (GVHD) after allogeneic transplantation using peripheral blood progenitor cells mobilized by granulocyte colony-stimulating factor (G-CSF) appear to be no worse than those after bone marrow transplantation, despite the presence of large numbers of T cells in the donor infusion. Experimental studies have shown that type-1 T cells (secreting interleukin-2 [IL-2] and interferon-gamma) mediate acute GVHD, whereas type-2 T cells (secreting IL-4 and IL-10) can prevent acute GVHD. We tested the hypothesis that G-CSF modulates T-cell function toward a type-2 response and thus reduces the severity of acute GVHD. B6 mice were injected with G-CSF or diluent for 4 days, and their splenic T cells were stimulated in vitro with alloantigen or mitogen in the absence of G-CSF. T cells from G-CSF-treated mice showed a significant increase in IL-4 production, with a simultaneous decrease in IL-2 and interferon-gamma production in response to both stimuli. We also examined the effect of G-CSF pretreatment of donors in a GVHD model (B6-->B6D2F1). Survival was significantly improved in recipients of G-CSF-treated donors. Concanavalin-A-induced cytokine production at day 13 after transplantation also showed an increase in IL-4 along with a decrease in IL-2 and IFN-gamma production by splenocytes from recipients of G-CSF-treated bone marrow and T cells. These data show that pretreatment of donors with G-CSF polarizes donor T cells toward the production of type-2 cytokines, which is associated with reduced type-1 cytokine production and reduced severity of acute GVHD.

Acute Disease↗
PubMed1995

The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma.

The genetic mechanisms underlying the genesis of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and their transformation into high-grade lymphoma are poorly understood. p53 inactivation, commonly caused by mutation and allele loss, has been shown to play an important role in the early development and/or the late disease progression of many human tumors including lymphoid malignancies and, thus, may also be important in MALT lymphomagenesis. We examined 75 cases (48 low grade and 27 high grade) of MALT lymphoma for p53 allele loss and mutation as well as protein accumulation. DNA samples prepared from microdissected cell populations were used for the detection of p53 gene abnormalities. Loss of heterozygosity (LOH) of the gene was detected by polymerase chain reaction-based analysis of p53 CA repeat polymorphism, whereas p53 mutation was studied by single-strand conformation polymorphism analysis and direct sequencing. p53 expression was assessed by immunostaining with CM1 polyclonal antibody. p53 allele loss and mutation, which resulted in the alteration in the amino acid sequence, were found in both low-grade (LOH, 3 of 44 [6.8%]; mutation, 9 of 48 [18.8%]) and high-grade (LOH, 6 of 21 [28.6%]; mutation, 9 of 27 [33.3%]) MALT lymphomas, particularly in the latter group. p53 staining was not observed in any low-grade tumors but in 6 high-grade cases that harbored missense mutations. There were also differences in the extent of p53 abnormalities, between low- and high-grade tumors. Of the 11 low-grade tumors showing p53 abnormalities, only 1 tumor showed the concomitance of p53 mutation and allele loss, whereas in high-grade tumors, 6 of 9 affected cases displayed both p53 mutation and allele loss. Our results suggest that p53 partial inactivation may play an important role in the development of low-grade MALT lymphomas, whereas complete inactivation may be associated with high-grade transformation.

Alleles↗
PubMed1995

On the role of ligand in retinoid signaling: positive cooperativity in the interactions of 9-cis retinoic acid with tetramers of the retinoid X receptor.

Previously, we have shown that the retinoid X receptor (RXR) forms tetramers with a high affinity and that interactions of the receptor with its ligand, 9-cis retinoic acid (9cRA), result in dissociation of protein tetramers. Here it is shown by fluorescence anisotropy studies that ligand-induced tetramer dissociation displays a pronounced positive cooperativity. The binding affinity of RXR for 9cRA at low saturation levels of the receptor with ligand was found to be significantly weaker than the affinity observed at higher levels of saturation. In addition, the rate of dissociation of 9cRA from RXR was found to be faster at low vs. high saturation levels of the receptor. These data suggest that the observed positive cooperativity of the ligand-induced dissociation of RXR tetramers stems from positive cooperativity in binding of 9cRA by the receptor. Kinetic studies showed that dissociation of RXR tetramers upon ligand binding is a rapid reaction characterized by a t1/2 of 80 ms, which is about 5 orders of magnitude faster than the rate of dissociation in the absence of ligand. The data indicate that the oligomeric state of RXR is tightly regulated by the precise concentrations of 9cRA and that it rapidly responds to changes in the ligand's concentrations. These findings further substantiate the hypothesis that modulation of the oligomeric state of RXR by 9cRA is an important regulatory step in the pathway by which retinoids affect gene transcription.

Fluorescence Polarization↗
PubMed1995

Role of ligand in retinoid signaling. 9-cis-retinoic acid modulates the oligomeric state of the retinoid X receptor.

Many of the effects of retinoids on cells are mediated by the transcription factors known as retinoid nuclear receptors, but the mechanisms by which retinoids regulate the activity of the receptors are not known. It was previously shown that the retinoid X receptor (RXR) forms tetramers with a high affinity. In the present work it is demonstrated that binding of 9-cis-retinoic acid to RXR leads to rapid dissociation of receptor tetramers. In addition, fluorescence anisotropy studies indicate that ligand-binding results in a significant conformational change such that holo-RXR is more compactly folded as compared to the apo-protein. These findings suggest that the initial event in signaling by 9-cis-retinoic acid is a change in the oligomeric state of RXR. The data also imply that tetramer formation is a regulatory feature of the pathway by which RXR mediates the effects of retinoids on gene transcription.

Binding Sites↗