Lactate and pH values in newborns with a history of acute fetal distress.

BACKGROUND: Acute fetal distress (AFD) is a condition that requires timely diagnosis because it generates hypoxia, acidosis, and even intrauterine death. This study aimed to determine lactate and pH values in the umbilical cord in full-term newborns (NBs) with a history of AFD. METHODS: We conducted a cross-sectional study in full-term NBs of mothers with at least one perinatal, neonatal, or gasometric AFD antecedent. Neonatal morbidity was considered: if 1-min Apgar ≤ 6, or advanced neonatal maneuvers, or neonatal intensive care unit (NICU) admissions were necessary. The cutoff points were lactate > 4mmol/L and pH < 7.2. RESULTS: Of 66 NBs, 33.3% of mothers presented at least one antecedent for developing AFD; 22.7% presented hypertensive pregnancy disease, 13.6% oligohydramnios, and 63.6% other factors. Perinatally, 28.7% required advanced neonatal resuscitation maneuvers and 7.5% admission to the NICU. In the gasometry, the lactate and pH values for the neonatal morbidity of the NBs' group were 4.726 ± 1.401 and 7.293 ± 0.056, respectively, versus 2.240 ± 0.318 and 7.359 ± 0.022 (p < 0.05) for the group without associated neonatal morbidity. CONCLUSIONS: Lactate values in the umbilical cord increased by 25%, and pH decreased by one percent in NBs with a history of AFD and associated morbidity.

INTRODUCCIÓN: El sufrimiento fetal agudo (SFA) es una condición que amerita un diagnóstico oportuno debido a que genera hipoxia, acidosis e incluso la muerte intrauterina. El objetivo de este estudio fue determinar los valores de lactato y pH en cordón umbilical en recién nacidos de término con antecedente SFA. MÉTODOS: Se llevó a cabo un estudio transversal, en recién nacidos a término, de madres que tuvieron al menos un antecedente para SFA de tipo perinatal, neonatal o gasométrico. Se consideró morbilidad neonatal cuando presentaron Apgar al minuto ≤ 6, o requirieron maniobras avanzadas de reanimación neonatal, o ingreso a Unidad de Cuidados Intensivos Neonatales (UCIN). El punto de corte fue > 4 mmol/L para los valores de lactato y pH < 7.2. RESULTADOS: De un total de 66 recién nacidos, el 33.3% de las madres presentaron al menos un antecedente para desarrollar SFA; el 22.7% presentó enfermedad hipertensiva del embarazo, el 13.6%, oligohidramnios, y el 63.6%, otros factores. El 28.7% requirieron maniobras avanzadas de la reanimación neonatal y el 7.5%, el ingreso a la UCIN. En la gasometría, el valor de lactato y pH para el grupo de recién nacidos con morbilidad neonatal fue de 4.726 ± 1.401 y 7.293 ± 0.056 respectivamente, versus 2.240 ± 0.318 y 7.359 ± 0.022 (p < 0.05) para el grupo sin morbilidad neonatal asociada. CONCLUSIONES: Se observó un incremento del 25% de los valores de lactato en cordón umbilical y una disminución del 1% del pH en los recién nacidos con antecedente de SFA y morbilidad asociada.

Lactate and pH values in newborns with a history of acute fetal distress / Valores de lactato y pH en recién nacidos con antecedente de sufrimiento fetal agudo

Abstract Background: Acute fetal distress (AFD) is a condition that requires timely diagnosis because it generates hypoxia, acidosis, and even intrauterine death. This study aimed to determine lactate and pH values in the umbilical cord in full-term newborns (NBs) with a history of AFD. Methods: We conducted a cross-sectional study in full-term NBs of mothers with at least one perinatal, neonatal, or gasometric AFD antecedent. Neonatal morbidity was considered: if 1-min Apgar ≤ 6, or advanced neonatal maneuvers, or neonatal intensive care unit (NICU) admissions were necessary. The cutoff points were lactate > 4mmol/L and pH < 7.2. Results: Of 66 NBs, 33.3% of mothers presented at least one antecedent for developing AFD; 22.7% presented hypertensive pregnancy disease, 13.6% oligohydramnios, and 63.6% other factors. Perinatally, 28.7% required advanced neonatal resuscitation maneuvers and 7.5% admission to the NICU. In the gasometry, the lactate and pH values for the neonatal morbidity of the NBs' group were 4.726 ± 1.401 and 7.293 ± 0.056, respectively, versus 2.240 ± 0.318 and 7.359 ± 0.022 (p < 0.05) for the group without associated neonatal morbidity. Conclusions: Lactate values in the umbilical cord increased by 25%, and pH decreased by one percent in NBs with a history of AFD and associated morbidity.

Resumen Introducción: El sufrimiento fetal agudo (SFA) es una condición que amerita un diagnóstico oportuno debido a que genera hipoxia, acidosis e incluso la muerte intrauterina. El objetivo de este estudio fue determinar los valores de lactato y pH en cordón umbilical en recién nacidos de término con antecedente SFA. Métodos: Se llevó a cabo un estudio transversal, en recién nacidos a término, de madres que tuvieron al menos un antecedente para SFA de tipo perinatal, neonatal o gasométrico. Se consideró morbilidad neonatal cuando presentaron Apgar al minuto ≤ 6, o requirieron maniobras avanzadas de reanimación neonatal, o ingreso a Unidad de Cuidados Intensivos Neonatales (UCIN). El punto de corte fue > 4 mmol/L para los valores de lactato y pH < 7.2. Resultados: De un total de 66 recién nacidos, el 33.3% de las madres presentaron al menos un antecedente para desarrollar SFA; el 22.7% presentó enfermedad hipertensiva del embarazo, el 13.6%, oligohidramnios, y el 63.6%, otros factores. El 28.7% requirieron maniobras avanzadas de la reanimación neonatal y el 7.5%, el ingreso a la UCIN. En la gasometría, el valor de lactato y pH para el grupo de recién nacidos con morbilidad neonatal fue de 4.726 ± 1.401 y 7.293 ± 0.056 respectivamente, versus 2.240 ± 0.318 y 7.359 ± 0.022 (p < 0.05) para el grupo sin morbilidad neonatal asociada. Conclusiones: Se observó un incremento del 25% de los valores de lactato en cordón umbilical y una disminución del 1% del pH en los recién nacidos con antecedente de SFA y morbilidad asociada.

Screening of CHO-K1 endogenous promoters for expressing recombinant proteins in mammalian cell cultures.

For the production of recombinant protein therapeutics in mammalian cells, a high rate of gene expression is desired and hence strong viral-derived promoters are commonly used. However, they usually induce cellular stress and can be susceptible to epigenetic silencing. Endogenous promoters, which coordinates their activity with cellular and bioprocess dynamics while at the same time they maintain high expression levels, may help to avoid such drawbacks. In this work, new endogenous promoters were discovered based on high expression levels in RNA-seq data of CHO-K1 cells cultured in high density. The promoters of Actb, Ctsz, Hmox1, Hspa5, Vim and Rps18 genes were selected for generating new expression vectors for the production of recombinant proteins in mammalian cells. The in silico-derived promoter regions were experimentally verified and the majority showed transcriptional activity comparable or higher than CMV. Also, stable expression following a reduction of culture temperature was investigated. The characterized endogenous promoters (excluding Rps18) constitute a promising alternative to CMV promoter due to their high strength, long-term expression stability and integration into the regulatory network of the host cell. These promoters may also comprise an initial panel for designing cell engineering strategies and synthetic promoters, as well as for industrial cell line development.

Dynamic regulation of CTCF stability and sub-nuclear localization in response to stress.

The nuclear protein CCCTC-binding factor (CTCF) has diverse roles in chromatin architecture and gene regulation. Functionally, CTCF associates with thousands of genomic sites and interacts with proteins, such as cohesin, or non-coding RNAs to facilitate specific transcriptional programming. In this study, we examined CTCF during the cellular stress response in human primary cells using immune-blotting, quantitative real time-PCR, chromatin immunoprecipitation-sequence (ChIP-seq) analysis, mass spectrometry, RNA immunoprecipitation-sequence analysis (RIP-seq), and Airyscan confocal microscopy. Unexpectedly, we found that CTCF is exquisitely sensitive to diverse forms of stress in normal patient-derived human mammary epithelial cells (HMECs). In HMECs, a subset of CTCF protein forms complexes that localize to Serine/arginine-rich splicing factor (SC-35)-containing nuclear speckles. Upon stress, this species of CTCF protein is rapidly downregulated by changes in protein stability, resulting in loss of CTCF from SC-35 nuclear speckles and changes in CTCF-RNA interactions. Our ChIP-seq analysis indicated that CTCF binding to genomic DNA is largely unchanged. Restoration of the stress-sensitive pool of CTCF protein abundance and re-localization to nuclear speckles can be achieved by inhibition of proteasome-mediated degradation. Surprisingly, we observed the same characteristics of the stress response during neuronal differentiation of human pluripotent stem cells (hPSCs). CTCF forms stress-sensitive complexes that localize to SC-35 nuclear speckles during a specific stage of neuronal commitment/development but not in differentiated neurons. We speculate that these particular CTCF complexes serve a role in RNA processing that may be intimately linked with specific genes in the vicinity of nuclear speckles, potentially to maintain cells in a certain differentiation state, that is dynamically regulated by environmental signals. The stress-regulated activity of CTCF is uncoupled in persistently stressed, epigenetically re-programmed "variant" HMECs and certain cancer cell lines. These results reveal new insights into CTCF function in cell differentiation and the stress-response with implications for oxidative damage-induced cancer initiation and neuro-degenerative diseases.

SARS-CoV-2 and RT-PCR in asymptomatic patients: Results of a cohort of workers at El Dorado International Airport in Bogotá, 2020 / [SARS-CoV-2 y RT-PCR en pacientes asintomáticos: resultados de una cohorte de trabajadores del Aeropuerto Internacional El Dorado de Bogotá, 2020].

Introduction: The 2019 coronavirus pandemic (COVID-19) has caused around 25 million cases worldwide. Asymptomatic patients have been described as potential sources of transmission. However, there are difficulties to detect them and to establish their role in the dynamics of virus transmission, which hinders the implementation of prevention strategies. Objective: To describe the behavior of asymptomatic SARS-CoV-2 virus infection in a cohort of workers at the El Dorado "Luis Carlos Galán Sarmiento" International Airport in Bogotá, Colombia. Materials and methods: A prospective cohort of 212 workers from the El Dorado airport was designed. The follow-up began in June, 2020. A survey was used to characterize health and work conditions. Every 21 day, a nasopharyngeal swab was taken to identify the presence of SARS-CoV-2 using RT-PCR. We analyzed the behavior of the cycle threshold (ORF1ab and N genes) according to the day of follow-up. Results: In the first three follow-ups of the cohort, we found an incidence of SARS-CoV-2 infection of 16.51%. The proportion of positive contacts was 14.08%. The median threshold for cycle threshold was 33.53. Conclusion: We characterized the asymptomatic SARS-CoV-2 infection in a cohort of workers. The identification of asymptomatic infected persons continues to be a challenge for epidemiological surveillance systems.

Introducción. La pandemia de COVID-19 ha ocasionado cerca de 25 millones de casos en el mundo. Se ha descrito que los pacientes asintomáticos pueden ser fuentes de transmisión. Sin embargo, es difícil detectarlos y no es claro su papel en la dinámica de transmisión del virus, lo que obstaculiza la implementación de estrategias para la prevención. Objetivo. Describir el comportamiento de la infección asintomática por SARS-CoV-2 en una cohorte de trabajadores del Aeropuerto Internacional El Dorado "Luis Carlos Galán Sarmiento" de Bogotá, Colombia. Materiales y métodos. Se diseñó una cohorte prospectiva de trabajadores del Aeropuerto El Dorado. El seguimiento se inició en junio de 2020 con una encuesta a cada trabajador para caracterizar sus condiciones de salud y trabajo. Cada 21 días se tomó una muestra de hisopado nasofaríngeo para detectar la presencia del SARS-CoV-2 mediante reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR). Se analizó el comportamiento del umbral del ciclo (cycle threshold) de los genes ORF1ab y N según el día de seguimiento. Resultados. En los primeros tres seguimientos de la cohorte se encontró una incidencia de la infección por SARS-CoV-2 del 16,51 %. La proporción de contactos positivos fue del 14,08 %. La mediana del umbral del ciclo fue de 33,53. Conclusión. Se determinaron las características de la infección asintomática por el SARSCoV-2 en una cohorte de trabajadores. La detección de infectados asintomáticos sigue siendo un reto para los sistemas de vigilancia epidemiológica.

SARS-CoV-2 y RT-PCR en pacientes asintomáticos: resultados de una cohorte de trabajadores del Aeropuerto Internacional El Dorado de Bogotá, 2020 / SARS-CoV-2 and RT-PCR in asymptomatic patients: Results of a cohort of workers at El Dorado International Airport in Bogotá, 2020

Introducción. La pandemia de COVID-19 ha ocasionado cerca de 25 millones de casos en el mundo. Se ha descrito que los pacientes asintomáticos pueden ser fuentes de transmisión. Sin embargo, es difícil detectarlos y no es claro su papel en la dinámica de transmisión del virus, lo que obstaculiza la implementación de estrategias para la prevención. Objetivo. Describir el comportamiento de la infección asintomática por SARS-CoV-2 en una cohorte de trabajadores del Aeropuerto Internacional El Dorado "Luis Carlos Galán Sarmiento" de Bogotá, Colombia. Materiales y métodos. Se diseñó una cohorte prospectiva de trabajadores del Aeropuerto El Dorado. El seguimiento se inició en junio de 2020 con una encuesta a cada trabajador para caracterizar sus condiciones de salud y trabajo. Cada 21 días se tomó una muestra de hisopado nasofaríngeo para detectar la presencia del SARS-CoV-2 mediante reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR). Se analizó el comportamiento del umbral del ciclo (cycle threshold) de los genes ORFlab y N según el día de seguimiento. Resultados. En los primeros tres seguimientos de la cohorte se encontró una incidencia de la infección por SARS-CoV-2 del 16,51 %. La proporción de contactos positivos fue del 14,08 %. La mediana del umbral del ciclo fue de 33,53. Conclusión. Se determinaron las características de la infección asintomática por el SARS-CoV-2 en una cohorte de trabajadores. La detección de infectados asintomáticos sigue siendo un reto para los sistemas de vigilancia epidemiológica.

Introduction: The 2019 coronavirus pandemic (COVID-19) has caused around 25 million cases worldwide. Asymptomatic patients have been described as potential sources of transmission. However, there are difficulties to detect them and to establish their role in the dynamics of virus transmission, which hinders the implementation of prevention strategies. Objective: To describe the behavior of asymptomatic SARS-CoV-2 virus infection in a cohort of workers at the El Dorado "Luis Carlos Galán Sarmiento" International Airport in Bogotá, Colombia. Materials and methods: A prospective cohort of 212 workers from the El Dorado airport was designed. The follow-up began in June, 2020. A survey was used to characterize health and work conditions. Every 21 day, a nasopharyngeal swab was taken to identify the presence of SARS-CoV-2 using RT-PCR. We analyzed the behavior of the cycle threshold (ORFlab and N genes) according to the day of follow-up. Results: In the first three follow-ups of the cohort, we found an incidence of SARS-CoV-2 infection of 16.51%. The proportion of positive contacts was 14.08%. The median threshold for cycle threshold was 33.53. Conclusion: We characterized the asymptomatic SARS-CoV-2 infection in a cohort of workers. The identification of asymptomatic infected persons continues to be a challenge for epidemiological surveillance systems.

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer.

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

Characterization of cellular states of CHO-K1 suspension cell culture through cell cycle and RNA-sequencing profiling.

Chinese hamster ovary (CHO) derived cell lines are the preferred host system for the production of therapeutic proteins. The aim of this work was to explore the regulation of suspension-adapted CHO-K1 host cell line bioprocesses, especially under a temperature gradient from 37 °C to 31 °C. We analyzed cell cycle behavior through flow cytometry of propidium iodide stained cells and high throughput transcriptome dynamics by RNA sequencing. We found a cell culture state characterized by G0/G1 synchronization, mainly during the late exponential growth phase and towards the last days of the stationary phase. We successfully identified key genes and pathways connected with the particular culture states, such as response to low temperature, modulation of the cell cycle, regulation of DNA replication and repair, apoptosis, among others. The most important gene expression changes occurred throughout the stationary phase when gene up-regulation markedly prevailed. Our RNA-seq data analysis enabled the identification of target genes for mechanism-based cell line engineering and bioprocess modification, an essential step to translate gene expression data from CHO-K1 host cells into bioprocess-related knowledge. Further efforts aim at increasing desirable phenotypes of CHO cells, and promoting efficient production of high quality therapeutic proteins can highly benefit from this type of studies.

Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer.

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.

Leprosy Drug Resistance Surveillance in Colombia: The Experience of a Sentinel Country.

An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1-88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively.

Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing.

The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drug-tolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.

Prevalence of antibodies for the hepatitis C virus in the lowland (bajio) region of Mexico.

BACKGROUND AND AIMS: Infection with the hepatitis C virus (HVC) is one of the most common viral infections worldwide. Approximately 170 million individuals are infected worldwide. HCV is an important cause of morbidity and mortality. In Mexico, according to the National Health Survey 2000, it is estimated that 70,000 cases exist. We undertook this study to estimate the prevalence of anti-HCV antibodies in patients with association to the risk factors for HCV infection in the lowland (bajio) region. METHODS: There were 2803 individuals 15 years of age or older who were treated at the General Hospital Zone #4 who were included in this study. Following informed consent, the participants were given a questionnaire listing the major risk factors for hepatitis C. If they answered positive to any of these identified factors, a blood sample was taken to determine anti-HCV antibodies via ELISA analysis. RESULTS: Average age in this study was 38.4 ± 13.5 years, and 75.5% were female (n = 2116). Anti-HCV antibodies were isolated in 1.3% of the patients (n = 36). The most commonly identified risk factor among all the participants was a history of previous transfusions (28.8 % of all patients, n = 813 and 41.7%, n = 15 of those with positive HCV antibodies). This was the only statistically significant risk factor identified in this study (p = 0.066). CONCLUSIONS: Mexico is currently considered to have a lower prevalence for HCV in relation to developed countries and other endemic areas. The figures reported are lower than those observed in this study, suggesting that the strategies for detecting HCV in Mexico may be inadequate.

Coordinate transcriptional and translational repression of p53 by TGF-ß1 impairs the stress response.

Cellular stress results in profound changes in RNA and protein synthesis. How cells integrate this intrinsic, p53-centered program with extracellular signals is largely unknown. We demonstrate that TGF-ß1 signaling interferes with the stress response through coordinate transcriptional and translational repression of p53 levels, which reduces p53-activated transcription, and apoptosis in precancerous cells. Mechanistically, E2F-4 binds constitutively to the TP53 gene and induces transcription. TGF-ß1-activated Smads are recruited to a composite Smad/E2F-4 element by an E2F-4/p107 complex that switches to a Smad corepressor, which represses TP53 transcription. TGF-ß1 also causes dissociation of ribosomal protein RPL26 and elongation factor eEF1A from p53 mRNA, thereby reducing p53 mRNA association with polyribosomes and p53 translation. TGF-ß1 signaling is dominant over stress-induced transcription and translation of p53 and prevents stress-imposed downregulation of Smad proteins. Thus, crosstalk between the TGF-ß and p53 pathways defines a major node of regulation in the cellular stress response, enhancing drug resistance.

A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function.

Kruppel-like transcription factors (KLFs) represent one of the most diverse set of regulators in vertebrate organisms. KLF family members are involved in cell proliferation and differentiation control in normal as well as in pathological situations. Here, we demonstrate that KLF6 behaves as a functional antagonist of the c-Jun proto-oncoprotein. Thus, KLF6 overexpression downregulated c-Jun-dependent transcription and a physical interaction between c-Jun and KLF6 was detected. Moreover, cell proliferation induced by c-Jun was significantly decreased by KLF6. The inhibition of c-Jun functions correlates directly with c-Jun protein degradation induced by KLF6. We also show that all KLF6 effects on c-Jun were largely dependent on phorbol ester (TPA/ionomycin) extracellular stimulation, which enhanced KLF6 nuclear translocation and transcriptional activity and modified its phosphorylation status. Our data are consistent with a novel mechanism of KLF6's role as an inhibitor of cell proliferation by counteracting the function of the c-Jun proto-oncoprotein involving enhanced c-Jun degradation by the proteasome-dependent pathway, and further reinforces KLF6 as a potential tumor suppressor gene product.