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Protein geranylgeranylation (GGylation) is an important biochemical process for many cellular signaling molecules. Previous studies have shown that GGylation is essential for cell survival in many types of cancer. However, the molecular mechanism mediating the cell survival effect remains elusive. In this report, we show that the Hippo pathway mediates GGylation-dependent cell proliferation and migration in breast cancer cells. Blockade of GGylation enhanced phosphorylation of Mst1/2 and Lats1, and inhibited YAP and TAZ activity and the Hippo-YAP/TAZ pathway-dependent transcription. The effect of GGylation blockade on inhibition of breast cancer cell proliferation and migration is dependent on the Hippo-YAP/TAZ signaling, in which YAP appears to regulate cell proliferation and TAZ to regulate cell migration. Furthermore, GGylation-dependent cell proliferation is correlated with the activity of YAP/TAZ in breast cancer cells. Finally, Gγ and RhoA are the GGylated proteins that may transduce GGylation signals to the Hippo-YAP/TAZ pathway. Taken together, our studies have demonstrated that the Hippo-YAP/TAZ pathway is essential for GGylation-dependent cancer cell proliferation and migration. [ABSTRACT FROM AUTHOR]

We report here a novel role for Jun dimerization protein-2 (JDP2) as a regulator of the progression of normal cells through the cell cycle. To determine the role of JDP2 in vivo, we generated Jdp2-knockout (Jdp2KO) mice by targeting exon-1 to disrupt the site of initiation of transcription. The epidermal thickening of skin from the Jdp2KO mice after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) proceeded more rapidly than that of control mice, and more proliferating cells were found at the epidermis. Fibroblasts derived from embryos of Jdp2KO mice proliferated faster and formed more colonies than fibroblasts from wild-type mice. JDP2 was recruited to the promoter of the gene for cyclin-A2 (ccna2) at the AP-1 site. Cells lacking Jdp2 had elevated levels of cyclin-A2 mRNA. Furthermore, reintroduction of JDP2 resulted in the repression of transcription of ccna2 and of cell-cycle progression. Thus, transcription of the gene for cyclin-A2 appears to be a direct target of JDP2 in the suppression of cell proliferation. [ABSTRACT FROM AUTHOR]

Ubiquitination is an important post-translational modification that has a pivotal role in numerous biological functions, such as cell growth, proliferation, apoptosis, DNA damage response, innate immune response and neuron degeneration. Although ubiquitination is thought to achieve these functions by targeting proteins for proteasome-dependent degradation, recent studies suggest that ubiquitination also has nonproteolytic functions, such as protein trafficking, kinase and phosphatase activation, which are involved in cell survival and cancer development. These progresses have advanced our current understanding of the novel functions of ubiquitination in signal transduction pathways and may provide novel paradigms for the treatment of human cancers. [ABSTRACT FROM AUTHOR]

Multiple genetic alterations are attributed to gastric cancer (GC); however, only a few critical genes have been identified so far. In this study, we isolated and characterized a novel gene p42.3, represented as tumor-specific and mitosis phase-dependent expression protein in GC cell line BGC823. Our data showed that the expression of p42.3 was cell cycle-dependent in GC cell lines. Moreover, p42.3 was specifically expressed in primary GC tissues but not in the matched normal mucosa of stomach, and this gene was expressed in diverse embryonic tissues. Furthermore, significant suppression of cell proliferation and tumorigenicity were detected and G2/M phase arrest was observed in cell line BGC823 depleted of p42.3 expression by RNAi technique, and we confirmed the expression changes of cyclin B1 and Chk2 following the silence of p42.3. Taken together, we cloned and characterized p42.3 gene that was specifically expressed in GC tumors but not in normal gastric mucosa, and the gene was associated with M-phase regulation. Moreover, p42.3 might be involved in cell proliferation and tumorigenesis; therefore, this gene might have potential applications in the diagnosis or treatment of GC.Oncogene (2007) 26, 7371–7379; doi:10.1038/sj.onc.1210538; published online 21 May 2007 [ABSTRACT FROM AUTHOR]