The role of dominant transforming p53 in carcinogenesis is poorly understood. Our previous data suggested that aberrant p53 proteins can enhance tumorigenesis and metastasis. Here, we examined potential mechanisms through which gain-of-function (GOF) p53 proteins can induce motility. Cells expressing GOF p53 -R175H, -R273H and -D281G showed enhanced migration, which was reversed by RNA interference (RNAi) or transactivation-deficient mutants. In cells with engineered or endogenous p53 mutants, enhanced migration was reduced by downregulation of nuclear factor-kappaB2, a GOF p53 target. We found that GOF p53 proteins upregulate CXC-chemokine expression, the inflammatory mediators that contribute to multiple aspects of tumorigenesis. Elevated expression of CXCL5, CXCL8 and CXCL12 was found in cells expressing oncogenic p53. Transcription was elevated as CXCL5 and CXCL8 promoter activity was higher in cells expressing GOF p53, whereas wild-type p53 repressed promoter activity. Chromatin immunoprecipitation assays revealed enhanced presence of acetylated histone H3 on the CXCL5 promoter in H1299/R273H cells, in agreement with increased transcriptional activity of the promoter, whereas RNAi-mediated repression of CXCL5 inhibited cell migration. Consistent with this, knockdown of the endogenous mutant p53 in lung cancer or melanoma cells reduced CXCL5 expression and cell migration. Furthermore, short hairpin RNA knockdown of mutant p53 in MDA-MB-231 cells reduced expression of a number of key targets, including several chemokines and other inflammatory mediators. Finally, CXCL5 expression was also elevated in lung tumor samples containing GOF p53, indicating relevance to human cancer. The data suggest a mechanistic link between GOF p53 proteins and chemokines in enhanced cell motility.

Let G be a finite group and let K be a hilbertian field. Many finite groups have been shown to satisfy the arithmetic lifting property over K, that is, every G-Galois extension of K arises as a specialization of a geometric branched covering of the projective line defined over K. The paper explores the situation when a semidirect product of two groups has this property. In particular, it shows that if H is a group that satisfies the arithmetic lifting property over K and A is a finite cyclic group then G l A M H also satisfies the arithmetic lifting property assuming the orders of H and A are relatively prime and the characteristic of K does not divide the order of A. In this case, an arithmetic lifting for any A 1 H-Galois extension of K is explicitly constructed and the existence of the arithmetic lifting for any G-Galois extension is deduced. It is also shown that if A is any abelian group, and H is the group with the arithmetic lifting property then A 1 H satisfies the property as well, with some assumptions on the ground field K. In the construction properties of Hilbert sets in hilbertian fields and spectral sequences in e! tale cohomology are used.

Abstract. Given a G-Galois extension of number fields L/K we ask whether it is a specialization of a regular G-Galois cover of P 1 K . This is the "inverse" of the usual use of the Hilbert Irreducibility Theorem in the Inverse Galois problem. We show that for many groups such arithmetic liftings exist by observing that the existence of generic extensions implies the arithmetic lifting property. We explicitly construct generic extensions for dihedral 2-groups under certain assumptions on the base field k. We also show that dihedral groups of order 8 and 16 have generic extensions over any base field k with characteristic different from 2.

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