The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-1. As aberrant activation of signal transducing molecules such as Ras and Raf-1 has been linked with cancer, we examined whether constitutive activation of the 41-/43-kDa MAP kinases is associated with the neoplastic phenotype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.2%) in a rather tissue-speci®c manner: cell lines derived from pancreas, colon, lung, ovary and kidney showed especially high frequencies with a high degree of MAP kinase activation, while those derived from brain, esophagus, stomach, liver and of hematopoietic origin showed low frequencies with a limited degree of MAP kinase activation. We also detected constitutive activation of the 41-/43-kDa MAP kinases in a relatively large number of primary human tumors derived from kidney, colon and lung tissues but not from liver tissue. Many tumor cells, in which point mutations of ras genes were detected, showed constitutive activation of MAP kinases, however, there were also many exceptions to this observation. In contrast, the activation of the 41-/43-kDa MAP kinases was accompanied by the activation of Raf-1 in the majority of tumor cells and was completely associated with the activation of MEK and p90 rsk in all the tumor cells examined. These results suggest that the constitutive activation of 41-/43-kDa MAP kinases in tumor cells is not due to the disorder of MAP kinases themselves, but is due to the disorder of Raf-1, Ras, or some other signaling molecules upstream of Ras.

A murine transcription factor, PEBP2, is composed of two subunits, a and ,B. There are two genes in the mouse genome, PEBP2aA and PEBP2&aB, which encode the at subunit. Two types of the aLB cDNA clones, aLBi and aB2, were isolated from mouse fibroblasts and characterized. They were found to represent 3.8-and 7.9-kb transcripts, respectively. The 3.8-kb RNA encodes the previously described aB protein referred to as oiBl, while the 7.9-kb RNA encodes a 387-amino-acid protein, termed aB2, which is identical to aBl except that it has an internal deletion of 64 amino acid residues. Both otBl and aB2 associate with PEBP2,I and form a heterodimer. The atB2/4 complex binds to the PEBP2 binding site two-to threefold more strongly than the aB1/,I complex does. aBl stimulates transcription through the PEBP2 site about 40-fold, while aB2 is only about 25 to 45% as active as aBl. Transactivation domain is located downstream of the 128-amino-acid runt homology region, referred to as the Runt domain. Mouse chromosome mapping studies revealed that aA, aB, and ,B genes are mapped to chromosomes 17, 16, and 8, respectively. The last two genes are syntenic with the human AMLI on chromosome 21q22 and PEBP24/CBFD on 16q22 detected at the breakpoints of characteristic chromosome translocations of the two different subtypes of acute myeloid leukemia. These results suggest that the previously described chimeric gene products, AML1/MTG8(ETO) and AMLl-EAP generated by t(8;21) and t(3;21), respectively, lack the transactivation domain of AMLL.A murine transcription factor, PEBP2, also called PEA2, was identified as a factor which binds to the region of the polyomavirus enhancer originally termed the PEA2 site (35). PEBP2 functionally cooperates with other enhancer corebinding proteins, including AP1 and Ets family proteins, PEA3 (48), , and PEBP5 (2), and plays an important role in stimulation of transcription and viral DNA replication. PEBP2 is composed of a and 3 subunits (32, 34). The at subunit bind to DNA by recognizing the consensus sequence, (Pu/T) ACCPuCA (13,34). The companion 3 subunit binds to the cx protein and increases the affinity of the a protein to DNA without binding to DNA by itself (32). cDNAs coding for both subunits have been cloned and characterized in detail (32, 34).PEBP2 has recently been shown to be closely related to acute myeloid leukemia (AML). The t(8;21)(q22;q22) translocation is one of the most frequent chromosome abnormalities in AML and is classified into the FAB-M2 subtype of AML (39). It has been shown that the t(8;21) breakpoints in the chromosome 21 are clustered in the recently described AMLI gene (27), the product of which shares a high homology within the 128-amino-acid (aa) region with the product of the Drosophila segmentation gene, runt (14), and the at subunit of PEBP2 (8,9,34 genome, oaB, which shares a high sequence homology with the original ao gene, termed aA. The aB gene as a whole is highly homologous to human AMLl (3). The discovery of the homology of the AML1 protein to the otsubunit o...

Our study suggests that cytoreductive surgery is beneficial to patients in whom pretreatment serum C-reactive protein is elevated. Particularly, those in whom serum C-reactive protein decreases to within normal limits may expect longer survival when surgery is combined with postoperative immunotherapy. Currently to our knowledge the prognostic factor that predicts postoperative nadir C-reactive protein has not been identified, indicating that cytoreductive surgery of the primary tumor should be performed in patients with elevated pretreatment C-reactive protein and as performance status permits.

The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter contains a consensus sequence for the polyomavirus enhancer binding-protein 2 (PEBP2) transcription factor, which consists of alpha and beta subunits. There are at least two genes, alpha A and alpha B, encoding the alpha subunit. alpha B is the mouse homologue of human AML1 gene detected at the breakpoints of t(8;21) and t(3;21) myeloid leukemias. We examined alpha A1 (an alpha A-gene product) and alpha B1 and alpha B2 (two alpha B-encoded isomers) for their effects on the GM- CSF promoter. PEBP2 alpha A1, alpha B1, and alpha B2 proteins bound the PEBP2 site within the mouse GM-CSF promoter. PEBP2 alpha A1 and alpha B1 enhanced the expression of the GM-CSF promoter-driven reporter plasmid in unstimulated and 12-O-tetradecanoylphorbol 13- acetate/phytohemagglutinin-stimulated human Jurkat T cells. In contrast, the promoter activity was suppressed by alpha B2. Coexpression of alpha B1 and alpha B2 showed that the promoter activity could be determined by the alpha B1/alpha B2 ratio. Jurkat cell extract contained PEBP2 site-binding protein(s) that cross-reacted with antimouse alpha A1 antibodies. Northern blot analysis indicated the expression of human PEBP2 alpha A, alpha B (AML1), and beta genes in Jurkat cells. Although further studies are required to determine the precise role of PEBP2 in the GM-CSF promoter activity, the present findings suggested the importance of the relative ratio of different PEBP2 isoforms in regulating the levels of the promoter activity.

BACKGROUND The androgen receptor (AR) gene has a polymorphic CAG microsatellite encoding variable‐length glutamine repeats in the AR protein. The purpose of this study was to evaluate the association between the growth of benign prostatic hyperplasia (BPH) and the AR gene CAG repeat length. METHODS We determined CAG repeat lengths in 176 BPH patients who underwent simple prostatectomy and in 41 control subjects without benign prostatic enlargement (non‐BPE group). RESULTS A statistically significant (P < 0.02) trend for large adenoma size with short CAG repeat length was found among the adenoma quartiles. CAG repeat length in the fourth quartile (large adenoma, 21.5 ± 2.7) was significantly shorter than in the first quartile (small adenoma, 23.3 ± 2.1, P < 0.02). It tended to be shorter than in the non‐BPE group (23.1 ± 2.4), but CAG repeat lengths in the entire BPH (22.4 ± 2.5) and non‐BPE groups did not significantly differ. The relative risk of large BPH (the fourth quartile) was 2.75 (95% confidence interval, 1.05–7.24; P < 0.05) on comparing CAG repeats of ≤22–≥23. CONCLUSIONS Shorter CAG alleles may be a genetic factor that promotes the growth of BPH. Prostate 41:253–257, 1999. © 1999 Wiley‐Liss, Inc.