In the pathogenesis of cervical carcinoma there are three major components, two of them related to the role of human papillomaviruses (HPV). First, the effect of viral E6 and E7 proteins. Second, the integration of viral DNA in chromosomal regions associated with well known tumour phenotypes. Some of these viral integrations occur recurrently at specific chromosomal locations, such as 8q24 and 12q15, both harbouring HPV18 and HPV16. And third, there are other recurrent genetic alterations not linked to HPV. Recurrent losses of heterozygosity (LOH) have been detected in chromosome regions 3p14–22, 4p16, 5p15, 6p21–22, 11q23, 17p13.3 without effect on p53, 18q12–22 and 19q13, all of them suggesting the alteration of putative tumour suppressor genes not yet identified. Recurrent amplification has been mapped to 3q+ arm, with the common region in 3q24–28 in 90% of invasive carcinomas. The mutator phenotype, microsatellite instability, plays a minor role and is detected in only 7% of cervical carcinomas. The development of cervical carcinoma requires the sequential occurrence and selection of several genetic alterations. The identification of the specific genes involved, and their correlation with specific tumour properties and stages could improve the understanding and perhaps the management of cervical carcinoma.

Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.

Variations in intracellular levels of p53 regulate many cellular functions and determine tumor susceptibility. Major mechanisms modulating p53 levels include phosphorylation and interaction of p53 with specific ubiquitin ligases that promote its degradation. N-terminal phosphorylation regulates the interaction of p53 with several regulatory molecules. Vaccinia-related kinase 1 (VRK1) is the prototype of a new Ser-Thr kinase family in the human kinome. VRK1 is located in the nucleus outside the nucleolus. Overexpression of VRK1 increases the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent of the Chk2 kinase. Catalytically inactive VRK1 protein (a K179E mutant) does not induce p53 accumulation. VRK1 phosphorylates human p53 in Thr18 and disrupts p53-Mdm2 interaction in vitro, although a significant decrease in p53 ubiquitination by Mdm2 in vivo was not detected. VRK1 kinase does not phosphorylate Mdm2. VRK1-mediated p53 stabilization was also detected in Mdm2^−/− cells. VRK1 also has an additive effect with MdmX or p300 to stabilize p53, and p300 coactivation and acetylation of p53 is enhanced by VRK1. The p53 stabilized by VRK1 is transcriptionally active. Suppression of VRK1 expression by specific small interfering RNA provokes several defects in proliferation, situating the protein in the regulation of this process. VRK1 might function as a switch controlling the proteins that interact with p53 and thus modifying its stability and activity. We propose VRK1 as the first step in a new pathway regulating p53 activity during cell proliferation.