Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase (Cancer Cell, 2010, 18:329-340)

報告日期: 2011/04/22
報告時間: 17:10/18:00
報告學生: 任婕羽 (英文報告)
講評老師: 呂佩融

Full Text:

Nuclear Cyclin D1/CDK4 Kinase Regulates CUL4 Expression and Triggers Neoplastic Growth via Activation of the PRMT5 Methyltransferase
Priya Aggarwal, Laura Pontano Vaites, Jong Kyong Kim, Hestia Mellert, Buddha Gurung, Hiroshi Nakagawa, Meenhard Herlyn, Xianxin Hua, Anil K. Rustgi, Steven B. McMahon, and J. Alan Diehl
Cancer Cell 2010 Oct;18:329-340
Speaker: 任婕羽
Commentator: 呂佩融老師
Time: 2011/4/22 17:10-18:00
Place: Room 602
 Cyclin D1, a regulator of CDK4, exhibits a strict expression pattern throughout the cell cycle to keep cell division normally. Aberrant cyclin D1 expression in S phase has been proved to lead to B cell lymphomas1 and mammary carcinomas2 in mice by interfering CUL4A/B transcription. CUL4A/B is a scaffold protein of E3 ligase that targets CDT1 for degradation during S phase. There’re lines of evidence showed that cyclin D1/CDK4-triggered repression of CUL4A/B increased CDT1 stability, disrupted S-phase fidelity, and therefore led to tumorigenesis3. However, how the aberrant cyclin D1/CDK4 expression leads to CUL4A/B transcriptional repression still remains unknown. To answer this question, these authors used mass spectrometry to identify cyclin D1/CDK4 interacting protein. Corresponding to the link of cyclin D1 and transcriptional repression, authors found that arginine methyltransferase 5 (PRMT5), a type II methyltransferase, and its coregulator, MEP50, associated with cyclin D1T286A/CDK4 (a lymphoid-specific cyclin D1 mutant that is stabilized in nucleus). These authors proved that cyclin D1T286A/CDK4 can phosphorylate MEP50 on threonine 5 residue, enhance PRMT5-dependent methylation on CUL4 promoters, and therefore cause CDT1 overexpression and DNA rereplication. Besides, these authors proved that mutant cyclin D1 E3 ligase, Fbx4, can also lead to cyclin D1 accumulation in nucleus and enhance PRMT5 methyltransferase activity. This line of evidence showed us that signaling mechanism of PRMT5 could be applied to other kinds of cyclin D1 aberrant expression not just lymphoid-specific cyclin D1 allele mutation. Collectively, these authors revealed that PRMT5/MEP50 is the downstream target of cyclin D1/CDK4 and its methyltransferase activity plays an important role in cyclin D1/CDK4-triggered neoplastic growth.
1.     Gladden, A.B. et al., Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma. Oncogene 25, 998-1007 (2006).
2.     Lin, D.I. et al., Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene 27, 1231-1242 (2008).
3.    Aggarwal, P. et al., Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication. Genes Dev. 21, 2908-2922 (2007).