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J. Biol. Chem., Vol. 279, Issue 12, 11639-11648, March 19, 2004

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Cyclin L2, a Novel RNA Polymerase II-associated Cyclin, Is Involved in Pre-mRNA Splicing and Induces Apoptosis of Human Hepatocellular Carcinoma Cells^*

Lianjun Yang, Nan Li, Chunmei Wang, Yizhi Yu, Liang Yuan, Minghui Zhang, and Xuetao Cao

From the Institute of Immunology, Second Military Medical University, Shanghai 200433, People's Republic of China

We report the cloning and functional characterization of human cyclin L2, a novel member of the cyclin family. Human cyclin L2 shares significant homology to cyclin L1, K, T1, T2, and C, which are involved in transcriptional regulation via phosphorylation of the C-terminal domain of RNA polymerase II. The cyclin L2 protein contains an N-terminal "cyclin box" and C-terminal dipeptide repeats of alternating arginines and serines, a hallmark of the SR family of splicing factors. A new isoform and the mouse homologue of human cyclin L2 have also been cloned in this study. Human cyclin L2 is expressed ubiquitously in normal human tissues and tumor cells. We show here that cyclin L2 co-localizes with splicing factors SC-35 and 9G8 within nuclear speckles and that it associates with hyperphosphorylated, but not hypophosphorylated, RNA polymerase II and CDK p110 PITSLRE kinase via its N-terminal cyclin domains. It can also associate with the SC-35 and 9G8 through its RS repeat region. Recombinant cyclin L2 protein can stimulate in vitro mRNA splicing. Overexpression of human cyclin L2 suppresses the growth of human hepatocellular carcinoma SMMC 7721 cells both in vitro and in vivo, inducing cellular apoptosis. This process involves up-regulation of p53 and Bax and decreased expression of Bcl-2. The data suggest that cyclin L2 represents a new member of the cyclin family, which might regulate the transcription and RNA processing of certain apoptosis-related factors, resulting in tumor cell growth inhibition and apoptosis.

Received for publication, July 9, 2003 , and in revised form, November 25, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY037150, AY116620 and AY337018.

^* This work was supported by National Natural Science Foundation of China 30121002, the National Key Basic Research Program of China 2001CB510002, and the National High Biotechnology Development Program of China 2002BA711A01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China. Fax: 86-21-6538-2502; E-mail: caoxt{at}public3.sta.net.cn.

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