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Aims/Background: The development of colorectal cancer depends on at least two distinct pathways involving genetic instability, namely: chromosome instability (CIN) and microsatellite instability. Cyclin E is involved in aneuploidy and several cancer types show an abnormal number of chromosomes. Methods: Cyclin E protein and mRNA values were analysed in human fetal skin fibroblasts and five colorectal cancer cell lines. Results: Cells with an aberrant number of chromosomes had higher cyclin E mRNA values and a significant increase in protein concentrations. Conclusions: These data suggest that cyclin E regulation is altered in aneuploid cells and is an important factor in the CIN pathway.

Cdk9 is a serine-threonine cdc2-related kinase and its activity is not cell cycle-regulated. Cdk9 function depends on its kinase activity and also on its regulatory units: the T-family cyclins and cyclin K. Recently, several studies confirmed the role of cdk9 in different cellular processes such as signal transduction, basal transcription, HIV-Tat- and MyoD-mediated transcription and differentiation. All the referred data strongly support the concept of a multifunctional protein kinase with specific cytoplasmic and nuclear functions.

Cyclin-dependent kinase 9 (cdk9) is a multifunctional kinase with roles in different cellular pathways such as transcriptional elongation, differentiation and apoptosis. Cdk9/cyclin T differs functionally from other cdk/cyclin complexes that regulate cell cycle progression, but maintains structural affinity with those complexes. In addition, previous reports have demonstrated that the cdk9 complex is able to phosphorylate p56/pRb in vitro. In this report we show in vitro and in vivo interaction between cdk9/cyclinT2 and the protein product of the retinoblastoma gene (pRb) in human cell lines. The interaction involves the region composed of residues 129–195 of cdk9, cyclinT2 (1–642 aa) and the C-terminal domain of pRb (835–928 aa). We located the minimal region of cdk9 phosphorylation on the C-terminus of pRb, by identifying the residues between 793 and 834. This region contains at least three proline-directed serines (sp), S795, S807 and S811, which have been reported to be phosphorylated in vivo and which could be targeted by the cdk9 complex. These data suggest that, in logarithmically growing cells, cdk9/cyclin T2 and pRb are located in a nuclear multiprotein complex probably involved in transduction of cellular signals to the basal transcription machinery and that one of these signals could be the cdk9 phosphorylation of pRb.

Editor—Hereditary non-polyposis colorectal cancer (HNPCC) is a heterogeneous autosomal dominant disease with incomplete penetrance. The frequency is estimated at 1:200/1:1000. HNPCC results from constitutional mutation in one of the five human mismatch repair genes (MMR) that have so far been implicated: hMSH2 , hMLH1 , hPMS1 , hPMS2 , and hMSH6 .1 2 hMSH2 and hMLH1 account for the majority of mutations found in HNPCC families (25-70%). The function of MMR genes is to maintain genetic stability and tumour DNA from HNPCC patients shows an accumulation of replication errors exhibiting an instability phenotype at microsatellite loci (MSI).3 4 Standard criteria have been established to define HNPCC clinically. These are known as the “Amsterdam criteria” and require that at least two generations be affected by colorectal cancer (CRC), that three or more relatives with histologically verified CRC be present, one of whom is a first degree relative of the other two, and at least one case of CRC be diagnosed before the age of 50.5 The syndrome is characterised by synchronous and metachronous CRC tumours and by association of certain types of extracolonic tumours, especially endometrial neoplasia.6 In 45-86% of cases,7 genetic testing characterises the mutation in the index patient for each HNPCC family identified and predicts a possible predisposition to colon and/or related syndrome cancer in at risk subjects of the same kindred. In clinical practice, however, besides HNPCC families, there are families with multiple CRC patients that do not fulfil the Amsterdam criteria, or with a single case of early onset CRC, or with multiple primary tumours. These features can suggest an HNPCC syndrome. In these instances, the percentage of germline mutations of MMR genes is low and the lifetime incidence of colorectal cancer is lower than in Amsterdam families.8 9 …