The drive to generate multiple forms of oncogenic cyclin D1 transcripts in mantle cell lymphoma

Abstract

Alternative polyadenylation is a rapidly emerging form of gene regulation, which in its simplest form, enables the generation of mRNA transcripts that code for the same protein but have 3'UTRs of different lengths and regulatory content. For oncogenes, shorter 3'UTRs would be preferred as a mechanism to evade miRNA regulation. The shortening of the 3'UTR of cyclin D1 in mantle cell lymphoma offers provocative insights into this process. Patient samples have revealed that 3'UTR shortening may occur due to mutations, or translocations that result in the generation of a chimeric 3'UTR. The truncated cyclin D1 3'UTRs resulting from alternative polyadenylation, use a premature canonical polyadenylation signal close to the stop codon that was generated either as a result of mutations or provided by another gene in the chimeric 3'UTR. The sequence of the polyadenylation signal in mantle cell lymphoma appears to be critical for 3'end formation of the cyclin D1 transcript. Shortening the 3'UTR allows cyclin D1 to potentially evade regulation by over 80 miRNAs that are predicted to bind to its full length 3'UTR.

Keywords: 3′UTR shortening; Alternative polyadenylation; Cyclin D1; Mantle cell lymphoma; Polyadenylation signal.

Fig. 1

The diversity of cyclin D1 transcripts in mantle cell lymphoma. This work is based on a previous publication [5]. a A schematic showing the location and sequences of all the potential polyadenylation signals (PAS) in full length CCND1 mRNA with the canonical polyadenylation signal (AAUAAA) at the most distal terminus. b Schematic of the PAS used in the alternative polyadenylation of the CCND1 in some MCL patients. The underlined letter (in red) is mutated in these patients to generate a canonical PAS. c The unaltered PAS which was identified in the Jeko-1 MCL cell line is shown and it is downstream of the other proximal hexamer. d A diagrammatic representation of the CCND1/MRCK fusion chimera showing the location of the MRCK sequence (in green) in the chimera and the PAS it contains

Fig. 2

Mantle cell lymphoma uses a different polyadenylation sequence than other cancer cells. a PCR products derived from 3′RACE of mRNA isolated from MCF7 and Jeko-1. C1 represents minus reverse transcriptase controls and C2 are controls minus the oligo(dT25)T7 primers. The blue line was inserted to highlight the slight difference in the size of the two 3′UTR transcripts. The method for 3′RACE was previously described [5]. b A partial sequence of the 3′UTR cDNA sequence derived from MCF7 compared to that of Jeko-1 showing the polyA tail (in green) for each transcript together with the PAS (underlined). Highlighted in yellow are differences in the nucleotide sequences between the two sequences, upstream of the first cleavage and polyadenylation site