Abstract
Tumor suppressor gene CYLD is a deubiquitinating enzyme which negatively regulates various signaling pathways by removing the lysine 63-linked polyubiquitin chains from several specific substrates. Loss of CYLD in different types of tumors leads to either cell survival or proliferation. In this study we demonstrate that lack of CYLD expression in CYLD−/− MEFs increases proliferation rate of these cells compared to CYLD+/+ in a serum concentration dependent manner without affecting cell survival. The reduced proliferation rate in CYLD+/+ in the presence of serum was due to the binding of serum response factor (SRF) to the serum response element identified in the CYLD promoter for the up-regulation of CYLD levels. The serum regulated recruitment of SRF to the CYLD promoter was dependent on p38 mitogen-activated protein kinase (MAPK) activity. Elimination of SRF by siRNA or inhibition of p38 MAPK reduced the expression level of CYLD and increased cell proliferation. These results show that SRF acts as a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of serum for aberrant proliferation of MEF cells.
Highlights
CYLD is a deubiquitinating enzyme (DUB) which is absent or strongly down regulated in different types of human cancer
We found an increase in the amount of CYLD+/+ cells in G1 phase and a decrease in G2/M phase compared to the CYLD2/2 mouse embryonic fibroblasts (MEFs) (Figure 1E)
CYLD is a DUB enzyme which is lost in different types of human cancer [8]
Summary
CYLD is a deubiquitinating enzyme (DUB) which is absent or strongly down regulated in different types of human cancer. The expression of CYLD is dramatically down-regulated in other types of human cancer such as melanoma [2], cervix cancer [3], colon cancer [4,5] and multiple myeloma [6,7]. CYLD deficient mice were highly sensitive to chemically induced skin tumors and developed significantly larger and faster-growing skin papillomas [10]. This effect was attributable to the elevated expression of cyclin D1 which caused an increase in the proliferation rate of CYLD-deficient keratinocytes than wild-type controls [10]. Even though previous studies has been highlighting the importance of post translational modifications of CYLD such as phosphorylation [11,12] and ubiquitination [13] for its tumor suppressor function, at the present there is a lack of knowledge of how CYLD transcription is regulated and by which signaling pathway this regulation occurs in non-transformed primary cells
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