Biologie Moléculaire et Cellulaire de la Signalisation, EA 3919, IFR 146, Université de Caen, Caen, France.
Mol Cancer. 2010 May 10;9:103. doi: 10.1186/1476-4598-9-103.
Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL). CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive.
To test the tumorigenic potential of cyclin D1b in vivo, we generated cell clones derived from the non-CCND1 expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a. Immunocompromised mice injected s.c. with LP-1K or LP-1D1b cells develop tumors at the site of injection. Genome-wide analysis of LP-1-derived cells indicated that several cellular processes were altered by cyclin D1b and/or cyclin K expression such as cell metabolism, signal transduction, regulation of transcription and translation. Importantly, cyclin K and cyclin D1b have no major action on cell cycle or apoptosis regulatory genes. Moreover, they impact differently cell functions. Cyclin K-expressing cells have lost their migration properties and display enhanced clonogenic capacities. Cyclin D1b promotes tumorigenesis through the stimulation of angiogenesis.
Our study indicates that cyclin D1b participates into MM pathogenesis via previously unrevealed actions.
细胞周期蛋白 D1 的异常表达是多发性骨髓瘤（MM）的一个常见特征，并且总是与套细胞淋巴瘤（MCL）相关。CCND1 基因可被选择性剪接，产生两种细胞周期蛋白 D1 mRNA 异构体，进而翻译为两种蛋白：细胞周期蛋白 D1a 和细胞周期蛋白 D1b。这两种异构体均存在于 MM 细胞系和原代细胞中，但它们在肿瘤发生过程中的相对作用仍不清楚。
为了在体内测试细胞周期蛋白 D1b 的致瘤潜能，我们从不表达 CCND1 的 MM LP-1 细胞系中生成了细胞克隆，这些细胞克隆分别合成细胞周期蛋白 D1b 或细胞周期蛋白 K，细胞周期蛋白 K 是细胞周期蛋白 D1a 的结构同源物和病毒致癌形式。将 LP-1K 或 LP-1D1b 细胞皮下注射免疫缺陷小鼠，会在注射部位形成肿瘤。对 LP-1 衍生细胞的全基因组分析表明，细胞周期蛋白 D1b 和/或细胞周期蛋白 K 的表达改变了几个细胞过程，如细胞代谢、信号转导、转录和翻译的调节。重要的是，细胞周期蛋白 K 和细胞周期蛋白 D1b 对细胞周期或细胞凋亡调节基因没有主要作用。此外，它们对细胞功能的影响也不同。表达细胞周期蛋白 K 的细胞丧失了迁移特性，并且具有增强的集落形成能力。细胞周期蛋白 D1b 通过刺激血管生成促进肿瘤发生。
我们的研究表明，细胞周期蛋白 D1b 通过以前未揭示的作用参与 MM 的发病机制。
