p53 is a 53-kDa nuclear protein that is associated with malignant transformation in several tumor model systems. In a survey of 134 human carcinomas, sarcomas, leukemias, and lymphomas obtained at surgery or from peripheral blood, we found rearrangements of the p53 gene only in osteogenic sarcomas (3 of 6 osteogenic sarcomas examined). Normal tissue from one of these patients had an unrearranged gene, indicating that the genetic abnormality in the tumor was acquired. Two of the sarcomas with rearranged genes expressed levels of p53 protein that were elevated relative to other tumors. Rearranged p53 genes were also found in human osteogenic sarcoma cell lines.

The CCAAT/enhancer binding protein ␣ (C/EBP␣) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBP␣ function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBP␣ gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelog- IntroductionThe CCAAT/enhancer binding protein ␣ (C/EBP␣) belongs to a family of proteins that possess a bipartite DNA-binding domain composed of a positively charged basic (b) region that contacts the DNA and a leucine zipper (ZIP) in the C terminus that mediates dimerization. 1 The less-conserved N terminus contains regulatory and transactivation domains. 2-5 C/EBP␣ is expressed in a number of tissues, most prominently in the highly differentiated cells of the liver, white and brown adipose, lung, and myeloid-lineage cells. [6][7][8][9] It has also been detected in the adrenal gland, skin, pancreas, prostate, differentiated enterocytes in the intestine, and, during follicular development, the ovary. [9][10][11][12] C/EBP␣ is proposed to be a regulator of energy metabolism and transcriptionally activates the promoters of energy-related genes such as GLUT4 and PEPCK in hepatocytes and adipocytes. [13][14][15] In myeloid cells, C/EBP␣ transcriptionally activates the promoters of the myeloid-specific receptors for the growth factors macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor. [16][17][18] Studies demonstrate that C/EBP␣ is critical for the process of terminal differentiation of adipocytes. C/EBP␣ is upregulated in adipocyte differentiation, and blocking its expression halts differentiation of preadipocytes into adipocytes, while overexpression induces differentiation and inhibits proliferation. [19][20][21][22][23] Also, overexpression of C/EBP␣ induces differentiation of myeloid leukemia cell lines and inhibits the proliferation of a number of cell lines and tumor cells. [24][25][26][27] The inhibition of proliferation is partly due to the ability of C/EBP␣ to activate transcription and induce posttranscriptional stabilization of the cyclin-dependent kinase inhibitor p21 (WAF-1). 28,29 These studies suggest a central role for C/EBP␣ in the regulation of cell proliferation and differentiation.Targeted inactivation of C/EBP␣ in mice demonstrates its importance in the proper development and function of liver, adipose, lung, and hematopoietic tissues. 8,30,31 Within 8 hours after birth, the mice die of impaired glucose metabolism, and adipose metabolism is altered with a failure of adipocytes to accumulate lipids. 30,31 The lung shows hyperproliferati...

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