[Corneal melt after intracorneal ring segment implantations: a case report].

A 50-year-old female patient presented to the Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Institute of Ophthalmology, with complaints of right eye pain, tearing, and difficulty opening the eye for over a month after intrastromal corneal ring segment (ICRS) implantation 18 years prior in both eyes. Slit lamp examination revealed corneal stromal melting around the ICRS at the 3 to 4 o'clock position of the right eye, with fluorescein staining. Optical coherence tomography showed epithelial and superficial stromal layer defects in the area of the lesion. The patient was diagnosed with corneal melting after ICRS implantation in the right eye. Under general anesthesia, the corneal stromal ring was removed, and deep lamellar keratoplasty was performed. The patient had no discomfort and the corneal graft remained transparent after the surgery.

[Analysis of long-term outcomes of penetrating keratoplasty for congenital corneal opacity].

Objective: To investigate the long-term outcomes of corneal grafts after penetrating keratoplasty(PK) for congenital corneal opacity(CCO) in children aged 0 to 5 years and the related influencing factors. Methods: It was a retrospective series case study. Data of 39 children (55 eyes) who underwent PK surgery due to CCO in the keratology Department of Beijing Tongren Hospital from April 2014 to April 2018 and were followed up for more than 30 months were collected. Among them, there were 17 males (43.6%) and 22 females (56.4%). The age at operation was (16.2±13.3) months, and the follow-up time was (46.4±13.8) months. Clinical data such as basic information, preoperative diagnosis, operation age, operation method and postoperative complications were recorded. The corneal graft transparency was analyzed according to preoperative diagnosis, corneal neovascularization area, age at surgery, monocular or binocular surgery interval, primary surgery type and further surgery, and postoperative complications were observed. Results: At 12 months, 24 months and the last follow-up after PK, 78.2% (43/55), 70.9% (39/55) and 58.2% (32/55) of the affected eyes had clear corneal grafts, respectively.There was no statistical significance between Peters anomaly and sclerocornea (P>0.05), while the extent of neovascularization in the limbus had a significant effect on corneal graft transparency, and graft opacity was more likely to occur in patients with vessel area exceeding 2 quadrants (P<0.05).The highest corneal graft transparency was found in children aged 1 to 3 years 80.8%(21/26) (P<0.05), followed by children younger than 6 months (7/15).The translucency rate of the corneal graft was higher in patients undergoing unilateral surgery than in those undergoing bilateral surgery (P<0.05).Translucency of corneal graft was higher in children with simple surgery than with combined surgery (P<0.05), however, cataract surgery after PK had no significant effect on corneal graft transparency (P>0.05).The postoperative complications mainly included immune rejection in 19 eyes (34.5%), complicated cataract in 13 eyes (23.6%), glaucoma in 7 eyes (13.2%), persistent corneal epithelial defect in 7 eyes (13.2%). Conclusions: After PK in children with CCO, the transparent rate of corneal grafts decreases gradually with time, but the long-term translucency of corneal grafts can still be obtained. The range of corneal neovascularization, age at the time of surgery, whether the surgery was binocular and whether the surgery was combined had an effect on the transparency of corneal graft.

[Clinical analysis of penetrating keratoplasty for infants with congenital corneal opacity].

Objective: To investigate the corneal graft survival and related risk factors of primary penetrating keratoplasty in congenital corneal opacity infants. Methods: It was a retrospective cohort study. Data were collected from forty-two infants (51 eyes) who were aged ≤12 months and diagnosed with congenital corneal opacity in Beijing Tongren Hospital and Beijing Anzhen Hospital from January 1, 2017 to January 31, 2018. The mean age at surgery was (5.7±2.2) months (3-12 months). The mean follow-up duration was (28.6±2.6) months (24-33 months). All the patients underwent penetrating keratoplasty. The status of the corneal grafts and complications were observed and recorded during the regular follow-up. The survival probabilities were estimated by using the Kaplan-Meier and Log-rank test. The graft survival between different influence factors was analyzed by using the χ2 test. Results: The Kaplan-Meier survival rates for penetrating keratoplasty were 84.3% (43/51) at 6 months, 78.4% (40/51) at 12 months and 60.8% (31/51) at the last follow-up. The presence of corneal neovascularization was significantly correlated with graft failure (χ²=5.264, P=0.022). The graft survival differed between eyes receiving combined surgery and mere penetrating keratoplasty and in eyes with varied surgical indications (P=0.039, <0.01). Increased intraocular pressure (7 eyes, 13.7%) and persistent epithelial defects (7 eyes, 13.7%) were the most common postoperative complications, followed by complicated cataract (4 eyes, 7.8%) and posterior capsule opacification (2 eyes, 3.9%). Conclusions: The graft survival rate was satisfactory following pediatric keratoplasty although it had a tendency to decrease with the follow-up time. Corneal neovascularization was a major risk factor of graft failure. Surgical indications and procedures also had a certain effect on the graft survival.

[Rational use of topical drugs to avoid drug-induced ocular surface injury].

Drug-induced ocular surface injury often occurs in the clinical diagnosis and treatment of eye diseases. Because of concealed clinical manifestations, it is difficult to be distinguished, causing misdiagnosis and mistreatment, and leading to serious corneal and conjunctival damage, and even visual disfunction. In this article, we focus on the mechanism, active prevention and effective treatment of drug-induced ocular surface injury, and propose that the rational use of local eye drugs can effectively reduce or avoid drug-induced ocular surface injury and improve the clinical diagnosis and treatment of eye diseases. (Chin J Ophthalmol, 2021, 57: 561-563).

[Preliminary observation on the treatment of primary pterygium with modified conjunctival transplantation and amniotic membrane transplantation combined with use of interferon eye drops].

Objective: To observe the clinical effect of modified conjunctival transplantation and amniotic membrane transplantation combined with use of interferon (IFN) alpha-2b eye drops in the treatment of primary pterygium. Methods: This was a prospective case-control study. Patients with primary pterygium were treated from June 1, 2018 to December 31, 2018 in the Department of Ophthalmology, Beijing Tongren Hospital, and they were divided into two groups (the experimental group and the control group) by the method of randomized block design. Patients in the experimental group received modified conjunctival transplantation and amniotic membrane transplantation combined with use of IFN alpha-2b eye drops, while patients in the control group received pterygium resection combined with conjunctival autograft transplantation. The pterygium type and size were observed before operation, while visual acuity, intraocular pressure and anterior segment details were recorded either. The follow-up was done at 1 week, 2 weeks, 1 month, 3 months, 6 months and 12 months after operation. The visual acuity, corneal epithelial defect, and pterygium recurrence were observed. All data in this manuscript are enumeration data, the expected frequency of pterygium type distribution in the two groups was more than 5, and the chi square test was used, fisher's exact test was used to compare the other data between the two groups. Results: Seventy patients (77 eyes) with pterygium were in this study, including 30 males and 40 females, aged from 50-70 years old. There were 35 cases (38 eyes) in the experimental group and 35 cases (39 eyes) in the control group. 12 months after operation there were 54 cases (60 eyes) including 28 cases (30 eyes) in the experimental group and 26 cases (30 eyes) in the control group with complete data. The corneal epithelium defects of 1 eye in each group was repaired within 7-14 days after operation, and the rest eyes were completely repaired within 7 days after operation. There was no significant difference in the distribution of corneal epithelial healing between the two groups (P= 1.00). There was no significant difference between the two groups in the number of eyes distribute with decreased visual acuity (2 eyes in each group), stable visual acuity (15 eyes in the experimental group and 23 eyes in the control group), and improved visual acuity (13 eyes in the experimental group and 5 eyes in the control group) (P=0.053). There was no recurrence in the two groups at 12 months after surgery, and there was no significant difference between the two groups in the number of patients with conjunctival hyperplasia of grades 1, 2 and 3 (P=0.405). Conclusions: Modified conjunctival transplantation and amniotic membrane transplantation combined with use of IFN alpha-2b eye drops got low recurrence rate for primary pterygium and less damage to the healthy conjunctival tissue. This combined treatment strategy provides a new choice for the treatment of pterygium. (Chin J Ophthalmol, 2020, 56: 768-773).

[The effectiveness and safety of topical 0.1% tacrolimus after high-risk penetrating keratoplasty].

Objective: To observe the effectiveness and safety of topical 0.1% tacrolimus(FK506) as immunosuppressant in high-risk penetrating corneal transplantation to prevent the immune rejection and to compare the outcomes with topical 1% Cyclosporin A (CsA). Methods: The study consists of 49 patients (50 eyes), who were fitted with the high-risk corneal transplantation standard and undergone the penetrating keratoplasty(PKP) or combined operation in Beijing Tongren hospital between March 2015 to September. With the time sequence, the patients were divided into observation group (FK506 group) and the control group (CsA group). The observation group included 9 females and 16 males with an average age of 57.8±14.8. Twenty-four patients were in the control group (25 eyes), including 10 females and 14 males, with an average age of (45.1±16.2). Observation group was treated with topical 0.1% tacrolimus, and the control group treated with topical 1%CsA. Both groups' treatment combined glucocorticoid as well. Two groups had 1 year follow-up observation. The incidence of rejection was compared by statistical methods of Cox regression. The adverse reactions were graded and compared using Mann-Whitney U test. Results: After one year, 22 cases of the observation group and 23 cases of the control group were accomplished all observations. The rejection rate was 4.54% in observation group and 27.23% in control group. The difference between the groups was statistically significant (χ(2)=4.291, P=0.038). Control group had high rejection rate. Besides, there was no severe side effects happened in both groups. After 1 month after surgery, 36.4% of the observation group showed mild corneal edema. The ratio of mild to moderate corneal edema in the control group was 26.1% and 8.7%. Three months after surgery, 4.5% of the observation group showed mild corneal edema, while 13.0% and 13.0% of the control group was found mild to moderate corneal edema. Six months after surgery, 4.5% of the observation group showed moderate corneal edema. The ratio of mild, moderate to severe corneal edema in the control group was 17.4%, 17.4% and 8.7%. The degree of corneal edema in the control group was more serious in three monthes(Z=-2.770, -2.018, -2.941, P<0.05). The differences in both monthes were statistically significant. Mild neovascularization occurred in the 13.6% of observation group. Mild to severe neovascularization occurred in the 13.0%, 4.3%, and 4.3% control groups. The degree of neovascularization in the control group was higher than that in the observation group(Z=-3.221, P=0.001). The differences in both months were statistically significant. Mild to moderate neovascularization occurred in the 18.2% and 9.1% of observation group. Mild to extremely severe neovascularization occurred in the 17.4%, 26.1%, 4.3% and 4.3% control groups. The degree of neovascularization in the control group was higher than that in the observation group(Z=-1.988, P=0.047).The differences in both monthes were statistically significant. Conclusions: Both 0.1% tacrolimus and 1% cyclosporine A are safe and effective in reducing the rejection after high-risk corneal transplantation. (Chin J Ophthalmol, 2019, 55: 419-427).

[Clinical observation of autologous simple limbal epithelial transplantation for unilateral limbal stem cell deficiency].

Objective: To discuss effect of autologous simple limbal epithelial transplantation (SLET) performed for unilateral limbal stem cell deficiency (LSCD). Methods: Retrospective case study. In this retrospective study, records of 7 patients (7 eyes) who had undergone autologous SLET for unilateral LSCD, with a minimum of 6 months of follow-up, were reviewed. Demographic details, etiology of LSCD, duration between ocular burn and SLET, prior surgery performed, presence or absence of symblepharon, pre-and post-operative visual acuity, and complications were noted. Results: Seven eyes of 7 patients underwent autologous SLET. With a follow-up of 6 months, a completely epithelialised and stable corneal surface was obtained in all recipient eyes. Visual acuity improved in all patients, while none of the eyes developed any complications. Conclusions: Autologous SLET is an effective and safe modality for treatment of unilateral LSCD. Clinical success rates and visual acuity improvement are equal to or better than those reported with earlier techniques. (Chin J Ophthalmol, 2019, 55:923-927).

[Clinical efficacy observation of atomization inhalation combined with oral administration of oseltamivir in 4 cases with H7N9 avian influenza].

Objective: To investigate the clinical efficacy of atomization inhalation combined with oral administration of oseltamivir in treatment of human infection with H7N9 avian influenza. Methods: To analyze the clinical data of 4 patients hospitalized from Mar 6th 2017 to Apr 12th 2017 with avian influenza(H7N9) infection treated by conventional therapy(oseltamivir, 150 mg, po, Bid) plus with oseltamivir inhalation(75 mg dissolved in 20 ml N. S, Bid) and administered with antibacterial treatment, blood purification and immunomodulators. Results: Undergoing these comprehensive therapies, Bronchial lavage fluid and pharynx of 1 case was negative for H7N9 RNA after 24 h, 2 cases negative for H7N9 after 3 d and 1 case negative for H7N9 RNA after 4 d. All patients were cured and discharged without any complications. Conclusions: Aseltamivir inhalation combined with oral treatment can significantly shorten the time of virus nucleic acid turning negative, improve the efficacy of anti avian influenza virus H7N9, and increase the cure rate of avian influenza H7N9 infection patients.

[Pay attention to the donor material supply for corneal transplantation].

Corneal transplantation is an important method in the treatment of corneal blindness. It is imperative to improve the treatment effectiveness of corneal disease and reduce the possibility of corneal blindness with the progress of corneal transplantation surgery, the construction and development of eye banks and the rational use of donor materials. This article reviews the component corneal transplantation technology promotion, eye bank construction and preparation of donor slices for component corneal transplantation surgery. (Chin J Ophthalmol, 2016, 52: 641-643).

[Antibody-based agents as experimental therapeutic interventions for corneal allograft rejection].

The corneal allograft rejection is the primary reason for graft failure, but the existing agents are of limited efficacy and may be accompanied by unacceptable morbidity. Recently, antibody-based agents have received great attention and have become an important part of therapeutic intervention for organ transplantation, which is also a research focus in the field of corneal transplantation. This review summarizes the history, current situation and mechanism of antibody-based agents in corneal transplantation.

Cullin1 is a novel marker of poor prognosis and a potential therapeutic target in human breast cancer.

BACKGROUND: To investigate the role of Cullin1 (Cul1) in the development of breast cancer, we examined the expression of Cul1 in breast cancer tissues and analyzed the correlation between Cul1 expression and clinicopathologic variables and patients survival. PATIENTS AND METHODS: We evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) which includes 393 breast cancer tissues. We also studied the role of Cul1 in breast cancer cell proliferation, migration and invasion by carrying out CCK8 cell proliferation assay, cell migration and invasion assay. RESULTS: The Cul1 expression was significantly correlated with breast cancer histology grade (P = 0.000), estrogen receptor status (P = 0.001), progesterone receptor status (P = 0.001) and human epidermal growth factor receptor 2 status (P = 0.002). Furthermore, we showed a strong correlation between high Cul1 expression and worse 5-year overall and disease-specific survival rates in breast cancer patients (P = 0.026 and P = 0.015, respectively). Finally, we found that Cul1 knockdown inhibits cell proliferation, migration and invasion abilities. CONCLUSIONS: Cul1 overexpression is significantly correlated with breast cancer progression and predicts worse survival. Cul1 regulates breast cancer cell proliferation, migration and invasion.

Assembly of functional U1 and U2 human-amphibian hybrid snRNPs in Xenopus laevis oocytes.

Oligonucleotides complementary to regions of U1 and U2 small nuclear RNAs (snRNAs), when injected into Xenopus laevis oocytes, rapidly induced the specific degradation of U1 and U2 snRNAs, respectively, and then themselves were degraded. After such treatment, splicing of simian virus 40 (SV40) late pre-mRNA transcribed from microinjected viral DNA was blocked in oocytes. If before introduction of SV40 DNA into oocytes HeLa cell U1 or U2 snRNAs were injected and allowed to assemble into small nuclear ribonucleoprotein particle (snRNP)-like complexes, SV40 late RNA was as efficiently spliced as in oocytes that did not receive U1 or U2 oligonucleotides. This demonstrates that oocytes can form fully functional hybrid U1 and U2 snRNPs consisting of human snRNA and amphibian proteins.

Identification of ubiquitin ligases required for skeletal muscle atrophy.

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

The SCF(HOS/beta-TRCP)-ROC1 E3 ubiquitin ligase utilizes two distinct domains within CUL1 for substrate targeting and ubiquitin ligation.

We describe a purified ubiquitination system capable of rapidly catalyzing the covalent linkage of polyubiquitin chains onto a model substrate, phosphorylated IkappaBalpha. The initial ubiquitin transfer and subsequent polymerization steps of this reaction require the coordinated action of Cdc34 and the SCF(HOS/beta-TRCP)-ROC1 E3 ligase complex, comprised of four subunits (Skp1, cullin 1 [CUL1], HOS/beta-TRCP, and ROC1). Deletion analysis reveals that the N terminus of CUL1 is both necessary and sufficient for binding Skp1 but is devoid of ROC1-binding activity and, hence, is inactive in catalyzing ubiquitin ligation. Consistent with this, introduction of the N-terminal CUL1 polypeptide into cells blocks the tumor necrosis factor alpha-induced and SCF-mediated degradation of IkappaB by forming catalytically inactive complexes lacking ROC1. In contrast, the C terminus of CUL1 alone interacts with ROC1 through a region containing the cullin consensus domain, to form a complex fully active in supporting ubiquitin polymerization. These results suggest the mode of action of SCF-ROC1, where CUL1 serves as a dual-function molecule that recruits an F-box protein for substrate targeting through Skp1 at its N terminus, while the C terminus of CUL1 binds ROC1 to assemble a core ubiquitin ligase.

p53 is phosphorylated by CDK7-cyclin H in a p36MAT1-dependent manner.

The tumor suppressor protein p53 acts as a transcriptional activator that can mediate cellular responses to DNA damage by inducing apoptosis and cell cycle arrest. p53 is a nuclear phosphoprotein, and phosphorylation has been proposed to be a means by which the activity of p53 is regulated. The cyclin-dependent kinase (CDK)-activating kinase (CAK) was originally identified as a cellular kinase required for the activation of a CDK-cyclin complex, and CAK is comprised of three subunits: CDK7, cyclin H, and p36MAT1. CAK is part of the transcription factor IIH multiprotein complex, which is required for RNA polymerase II transcription and nucleotide excision repair. Because of the similarities between p53 and CAK in their involvement in the cell cycle, transcription, and repair, we investigated whether p53 could act as a substrate for phosphorylation by CAK. While CDK7-cyclin H is sufficient for phosphorylation of CDK2, we show that p36MAT1 is required for efficient phosphorylation of p53 by CDK7-cyclin H, suggesting that p36MAT1 can act as a substrate specificity-determining factor for CDK7-cyclin H. We have mapped a major site of phosphorylation by CAK to Ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. Both wild-type and tumor-derived mutant p53 proteins are efficiently phosphorylated by CAK. Furthermore, we show that p36 and p53 can interact both in vitro and in vivo. These studies reveal a potential mechanism for coupling the regulation of p53 with DNA repair and the basal transcriptional machinery.

Mutations in conserved regions of the predicted RAG2 kelch repeats block initiation of V(D)J recombination and result in primary immunodeficiencies.

The V(D)J recombination reaction is composed of multiple nucleolytic processing steps mediated by the recombination-activating proteins RAG1 and RAG2. Sequence analysis has suggested that RAG2 contains six kelch repeat motifs that are predicted to form a six-bladed beta-propeller structure, with the second beta-strand of each repeat demonstrating marked conservation both within and between kelch repeat-containing proteins. Here we demonstrate that mutations G95R and DeltaI273 within the predicted second beta-strand of repeats 2 and 5 of RAG2 lead to immunodeficiency in patients P1 and P2. Green fluorescent protein fusions with the mutant proteins reveal appropriate localization to the nucleus. However, both mutations reduce the capacity of RAG2 to interact with RAG1 and block recombination signal cleavage, therefore implicating a defect in the early steps of the recombination reaction as the basis of the clinical phenotype. The present experiments, performed with an extensive panel of site-directed mutations within each of the six kelch motifs, further support the critical role of both hydrophobic and glycine-rich regions within the second beta-strand for RAG1-RAG2 interaction and recombination signal recognition and cleavage. In contrast, multiple mutations within the variable-loop regions of the kelch repeats had either mild or no effects on RAG1-RAG2 interaction and hence on the ability to mediate recombination. In all, the data demonstrate a critical role of the RAG2 kelch repeats for V(D)J recombination and highlight the importance of the conserved elements of the kelch motif.

Scope of radiological protection control measures.

In this report, the Commission recommends approaches to national authorities for their definition of the scope of radiological protection control measures through regulations, by using its principles of justification and optimisation. The report provides advice for deciding the radiation exposure situations that should be covered by the relevant regulations because their regulatory control can be justified, and, conversely, those that may be considered for exclusion from the regulations because their regulatory control is deemed to be unamenable and unjustified. It also provides advice on the situations resulting from regulated circumstances but which may be considered by regulators for exemption from complying with specific requirements because the application of these requirements is unwarranted and exemption is the optimum option. Thus, the report describes exclusion criteria for defining the scope of radiological protection regulations, exemption criteria for planned exposure situations, and the application of these concepts in emergency exposure situations and in existing exposure situations. The report also addresses specific exposure situations such as exposure to low-energy or low-intensity adventitious radiation, cosmic radiation, naturally occurring radioactive materials, radon, commodities, and low-level radioactive waste. The quantitative criteria in the report are intended only as generic suggestions to regulators for defining the regulatory scope, in the understanding that the definitive boundaries for establishing the situations that can be or need to be regulated will depend on national approaches.

Demographic Characteristics of Voluntary Donors Registered in Beijing Tongren Hospital Eye Bank of China: A Retrospective Study From 2007 to 2016.

BACKGROUND: Lack of willingness to pledge eyes among the general population is the main cause for the shortage of cornea tissue in China. A few studies have implied that general-population adults with specific demographics showed more willingness to donate their eyes. METHODS: In this study, we analyzed the demographic characteristics of 918 voluntary donors registered in Beijing Tongren Hospital Eye Bank in the past 10 years for possible predictors that might help us to identify potential donors in Beijing and increase the donation rate. All copies of voluntary eye donation application forms filled by the registrants from 2007 to 2016 were collected. Basic demographics listed in the application form were extracted for analysis. Demographics were described as proportions and compared by means of a χ2 test. Besides that, donor counts and proportions of combining 2 demographics from the 4 main demographics were described and compared. RESULTS: Voluntary donors greater than 50 years of age (n = 477, 53.0%) predominated the proportions. Regarding education level and occupation, donors with tertiary education (n = 484, 57.4%) were more numerous than donors with primary and secondary education (n = 355, 42.1%); office clerks, workers, and government officers were more willing to pledge eyes than were donors engaged in other occupations. In addition, donors of the Han race (n = 856, 94.9%) made up the majority and mainly were distributed in 5 central administrative districts of Beijing (n = 629, 77.5%). CONCLUSIONS: The present study suggests that older women (>50 years of age), living in a central district, with higher education level and engaged in white-collar work, were possible predictors for potential donors.

HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin.

SCF E3 ubiquitin ligases mediate ubiquitination and proteasome-dependent degradation of phosphorylated substrates. We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo. This targeting required Cullin1 as expression of a mutant Cullin1 abrogated the degradation of IkappaB and of beta-catenin. Mutant HOS which lacks the F-box blocked TNF alpha-induced degradation of IkappaB as well as GSK3beta-mediated degradation of beta-catenin. This mutant also inhibited NF-kappaB transactivation and increased the beta-catenin-dependent transcription activity of Tcf. These results demonstrate that SCF(HOS) E3 ubiquitin ligase regulate both NF-kappaB and beta-catenin signaling pathways.

The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E.

The promyelocytic leukemia protein (PML) is a mammalian regulator of cell growth which is characteristically disrupted in acute promyelocytic leukemia and by a variety of viruses. PML contains a RING domain which is required for its growth-suppressive and antiviral properties. Although normally nuclear, in certain pathogenic conditions, including arenaviral infection, PML is relocated to the cytoplasm, where its functions are poorly understood. Here, we observe that PML and arenavirus protein Z use regions around the first zinc-binding site of their respective RING domains to directly interact, with sub-micromolar affinity, with the dorsal surface of translation initiation factor eIF4E, representing a novel mode of eIF4E recognition. PML and Z profoundly reduce the affinity of eIF4E for its substrate, the 5' 7-methyl guanosine cap of mRNA, by over 100-fold. Association with the dorsal surface of eIF4E and direct antagonism of mRNA cap binding by PML and Z lead to direct inhibition of translation. These activities of the RING domains of PML and Z do not involve ubiquitin-mediated protein degradation, in contrast to many RINGs which have been observed to do so. Although PML and Z have well characterized physiological functions in regulation of growth and apoptosis, this work establishes the first discrete biochemical mechanism which underlies the biological activities of their RING domains. Thus, we establish PML and Z as translational repressors, with potential contributions to the pathogenesis of acute promyelocytic leukemia and variety of viral infections.