Cul4A is an oncogene in malignant pleural mesothelioma

Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Journal of Cellular and Molecular Medicine (Impact Factor: 3.7). 11/2009; 15(2):350-8. DOI: 10.1111/j.1582-4934.2009.00971.x
Source: PubMed

ABSTRACT Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

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Available from: Yu-Ching Lin, Aug 19, 2015
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    • "The cullins are a family of eight members, which do not have intrinsic catalytic activity, when acting alone, but instead are molecular scaffolds that facilitate the assembly of modular CRL complexes and mediate the transfer of ubiquitin from the E2-conjugating enzyme to the substrate proteins [22]. Cullin 1 is overexpressed in 40% of lung cancers [84], whereas cullin 4A expression is elevated in multiple cancer types, such as breast [85] [86] [87], hepatocellular [88], and mesothelioma [89]. Overexpression of cullin 4A in MCF10A cells abrogated the G2/M cell cycle checkpoint in response to radiation-induced DNA damage [90]. "
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    • "It does so by orchestrating the concerted actions of nucleotide excision repair (NER) and the DNA damage-responsive G1/S checkpoint through selective degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector (Liu et al., 2009). We previously found that Cul4A is an oncogene for mesothelioma (Hung et al., 2009). However, the relationship between Cul4A and the occurrence and metastasis of other tumors such as mesothelioma and lung cancer is seldom reported, and the potential oncogenic role of Cul4A has been little studied. "
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