Inactivation of p53 tumor suppressor gene acts synergistically with c-neu oncogene in salivary gland tumorigenesis.
Transgenic mice expressing specific oncogenes usually develop tumors in a stochastic fashion suggesting that tumor progression is a multi-step process. To gain further understanding of the interactions between oncogenes and tumor suppressor genes during tumorigenesis, we have crossed a transgenic strain (TG.NK) carrying an activated c-neu oncogene driven by the MMTV enhancer/promoter with p53-deficient mice. c-neu transgenic mice have stochastic breast tumor formation and normal appearing salivary glands. However, c-neu mice heterozygous for a p53 deletion develop parotid gland tumors and loose their wild type p53 allele. c-neu mice with a homozygous p53 deletion have increased rates of parotid tumor onset suggesting that inactivation of p53 is required and sufficient for parotid gland transformation in the presence of activated c-neu. In contrast to the dramatic effect of p53 in parotid gland transformation, p53 loss has little effect on the rate or stochastic appearance of mammary tumors. In addition, p53 loss was accompanied by the down regulation of p21 in parotid gland tumors but not breast tumors. The parotid gland tumors were aneuploid and demonstrated increased levels of Cyclin D1 expression. These observations suggest that in c-neu transgenic mice, p53 alterations have differential tissue effects and may be influenced by the tissue specific expression of genes influencing p53 activity.
Brodie
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SG
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
Xu
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Li
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Kuo
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Leder
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Deng
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D000782:Aneuploidy; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019938:Cyclin D1 / Q000302:isolation & purification; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000302:isolation & purification; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D016158:Genes, p53; D019656:Loss of Heterozygosity; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010307:Parotid Neoplasms / Q000235:genetics; D012468:Salivary Gland Neoplasms / Q000209:etiology / Q000235:genetics*; D012469:Salivary Glands / Q000378:metabolism; D013269:Stochastic Processes; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000302:isolation & purification
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1