The p53 protein suppresses tumorigenesis by initiating cellular functions such as cell cycle arrest and apoptosis in response to DNA damage. A p53 mutant, p53R172P, which is deficient for apoptosis but retains a partial cell cycle arrest function, delays tumor onset in mice. Remarkably, lymphomas arising in Trp53 515C/515C mice (encoding p53R172P) retain stable genomes. Given the dominant role of p21 in p53 cell cycle control, we crossed Trp53 515C/515C mice onto a p21-null background to determine whether p21 was required for maintaining chromosomal stability and delaying tumor onset. Loss of p21 completely abolished the cell cycle arrest function of p53R172P and accelerated tumor onset in Trp53 515C/515C mice. Cytogenetic examination of Trp53 515C/515C p21 ؊/؊ sarcomas and lymphomas revealed aneuploidy and chromosomal aberrations that were absent in Trp53 515C/515C malignancies. Thus, p21 coupled p53-dependent checkpoint control and preservation of chromosomal stability, and cooperated with apoptosis in suppressing tumor onset in mice.apoptosis ͉ chromosomal instability ͉ p53 ͉ tumorigenesis ͉ mouse model T he role of p53 in tumor suppression is well established.

Mutational inactivation of p53 is a hallmark of most human tumors. Loss of p53 function also occurs by overexpression of negative regulators such as MDM2 and MDM4. Deletion of Mdm2 or Mdm4 in mice results in p53-dependent embryo lethality due to constitutive p53 activity. However, Mdm2 À/À and Mdm4 À/À embryos display divergent phenotypes, suggesting that Mdm2 and Mdm4 exert distinct control over p53. To explore the interaction between Mdm2 and Mdm4 in p53 regulation, we first generated mice and cells that are triple null for p53, Mdm2, and Mdm4. These mice had identical survival curves and tumor spectrum as p53 À/À mice, substantiating the principal role of Mdm2 and Mdm4 as negative p53 regulators. We next generated mouse embryo fibroblasts null for p53 with deletions of Mdm2, Mdm4, or both; introduced a retrovirus expressing a temperature-sensitive p53 mutant, p53A135V; and examined p53 stability and activity.

The p53 tumor suppressor is mutated in the majority of human tumors. MDM2, a well-known inhibitor of p53, is overexpressed in a large number of tumors suggesting that increased levels of MDM2 also contribute to tumorigenesis. A novel p53 inhibitor, MDM4, was more recently identified. The role of MDM4 in cancer development is not well understood. We set out to examine the levels of MDM4 by immunohistochemistry in Head and Neck Squamous Carcinomas (HNSC) to ask whether high MDM4 levels could contribute to its development and progression. In addition, MDM2 and p53 levels were examined to identify overlapping expression patterns. MDM4 is present at high levels in 50% of HNSC. Additionally, overexpression of MDM2 was detected in 80% of tumors, many of which were also positive for MDM4. A subset of tumors displayed high levels of all three proteins. Sequencing of the p53 gene revealed that tumors with positive immunoreactivity for MDM2 or MDM4, some of which also had high levels of p53, did not carry mutations in this gene. Thus, the detection of p53 by immunohistochemistry was not synonymous with the presence of p53 mutations. Expression of both MDM2 and MDM4 in tumors without p53 mutations strongly suggests that MDM2 and MDM4 inhibit the activity of this tumor suppressor in HNSC.

Human homolog of murine double minute 2 (HDM2) and HDM4 (or HDMX) are negative regulators of p53. HDM4 has not been assessed in precursor B (pre-B) lymphoblastic leukemia (ALL). We examined bone marrow samples obtained at time of diagnosis from 55 adults with pre-B ALL. A tissue microarray composed of 2 cores per specimen was constructed and immunohistochemical techniques were used to assess HDM4, HDM2, p53, and p21. HDM4 was expressed in 39 of 49 (80%) cases. HDM2 was expressed in 14 of 54 (26%). All HDM2-positive cases were also positive for HDM4 (Po0.05). We confirmed expression of HDM4 and HDM4 variants by Western blotting and sequencing of reverse transcription-polymerase chain reaction products in a subset of ALL tumors. Results were correlated with the presence of the Philadelphia chromosome (Ph). p53 (Po0.05) and p21 (Po0.001) were expressed significantly more often in Ph þ pre-B ALL. HDM4 and HDM2 showed no correlation with Ph status. HDM4 expression in most cases of adult pre-B ALL suggests that HDM4 is a potential therapeutic target. Modern Pathology (2007) 20, 54-62.

Stats are latent transcription factors involved in normal cellular signaling in response to cytokine or growth factor stimulation. Constitutive activation of Stats (primarily Stat3 and Stat5) has been implicated in growth dysregulation and oncogenesis. Furthermore, increased activation of Stats has been observed in several human tumors and tumor-derived cell lines. To assess the contribution of aberrant Stat activation in oncogenesis, we have created a chimeric molecule between Stat3beta and a portion of the Herpes simplex virus VP16 activation domain. The resulting protein, Stat3beta-VAD (VP16 activation domain), is tyrosine phosphorylated on Y705 and can bind DNA in the absence of upstream activation by c-Src or epidermal growth factor (EGF). Unlike Stat3alpha and Stat3beta, Stat3beta-VAD robustly activates transcription of several reporter genes without cytokine or growth factor stimulation. In addition, we show marked upregulation of the endogenous c-myc and c-fos genes upon inducible expression of Stat3beta-VAD in COS-7 cells. Our protein displays the constitutive transcriptional activation of Stat3alpha seen in human tumors and will be a valuable tool in screens for Stat3-regulated genes. In response to the established Stat3 involvement in human cancers, Stat3beta-VAD will also facilitate assessing the contribution of other cancer signaling cascades in the context of aberrant Stat3alpha activity in cancer development and progression.

ResumenSe describen los aportes que el estudio de clase brinda a los procesos de formación inicial y cualificación docente en el área de matemáticas. Se explora también las conexiones teóricas plausibles que se pueden generar entre la metodología estudio de clase, la investigación formativa y el conocimiento didáctico del contenido. La metodología empleada se enmarca en el paradigma de investigación cualitativo, privilegiando los alcances descriptivos y exploratorios, mediante la aplicación de la metodología de estudio de clase, con sus fases de indagación-planeación, ejecución-observación y revisión-reflexión. Los resultados evidencian como el estudio de clase favorece ampliamente la cualificación y desarrollo del conocimiento profesional de los profesores, permitiendo establecer una adecuada relación entre el conocimiento disciplinar, pedagógico, didáctico e investigativo. Palabras clave: estudio de clase, estrategia docente, cualificación docente, investigación formativaThe class study, methodology as a strategy and scenario for the mathematics' teacher qualification AbstractThe study describes the contribution that the class study methodology provides to the initial training processes and the teachers qualification in the mathematics area teaching. Also, some valid theoretical connections that can be generated among the class study methodology, the formative research and the knowledge of the educational content are explored. The research methodology can be included in the qualitative paradigm, favoring the descriptive and exploratory scope through the application of a class study methodology and its stages of inquiry-planning, execution-observation and revision-analysis. The results show how the class study favors the qualification and development of the teachers' professional knowledge, allowing establishing an appropriate relation among the academic, pedagogical, educational and investigative knowledge.

Criterios emergentes y asociados a la idoneidad didáctica para la enseñanza del perímetro Barboza

ResumenSe han analizado y caracterizado los tipos de problemas aritméticos, que formulan los estudiantes del programa de Licenciatura en Matemáticas de la Universidad de Sucre. El tipo de estudio fue descriptivo e interpretativo y se tomó una muestra de 39 estudiantes de séptimo y octavo semestre. Se aplicó un cuestionario que indagó sobre su pensamiento aritmético, en particular sobre la redacción de los problemas de estructura aditiva. Los resultados muestran, que los problemas planteados por los estudiantes, son en su mayoría de tipo verbal y numérico, siendo escasos los del tipo gráfico. Además 80% de los problemas, son sólo formulados, desde una sola estructura semántica; en este caso la de estructura de cambio, ubicando siempre la pregunta al final. El estudio evidencia, el desconocimiento de los estudiantes, con respecto al campo de las estructuras aditivas y en especial la formulación de situaciones problemas para el nivel de escuela básica primaria, donde les corresponderá enseñar en el futuro. Palabras claves: formación; docentes; problemas; aritmética; estructura aditiva Arithmetic Thinking in Undergraduate Students in Mathematics at the University of Sucre AbstractArithmetical problems, which were designed by students of the undergraduate program in mathematics at the University of Sucre were analyzed and characterized. The study was of the type descriptive and interpretative and a sample group of 39 students in the seventh and eighth semester. A questionnaire that asked about their arithmetical thought, in particular on the wording of the additive structure problems was applied. The results show that the problems proposed by students are mostly verbal and numerical, being scarcely of the graphic type. Also, 80% of problems are only formulated from a single semantics frame; in this case the structure of change, placing the question always at the end. The report evidences the students' lack of awareness of the field of additive structures, and especially of the formulation of problem situations, for the basic level of primary school, where they will have to teach in the future.