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  • The notion that a small subset of inducible cellular

    2020-10-13

    The notion that a small subset of inducible cellular transcripts, encoding immunological important factors, is translocated across the nuclear envelope by the karyopherin CRM1 is gaining support from various recent studies. For example, experimental evidence has been provided demonstrating that the transcripts coding for interferon-α1, TNFα or lymphotoxin α are subject to CRM1 regulation (Schütz et al. 2006; Kimura et al. 2004). Interestingly, CRM1-regulated mRNAs are extremely rare as opposed to the abundance of cellular transcripts transported by the unrelated Tap/NXF1 pathway (Izaurralde 2004; Erkmann and Kutay 2004; Hutten and Kehlenbach 2007), and are frequently recognized by the cellular RNA binding shuttle protein HuR (Brennan et al. 2000; Keene 1999; Jang et al. 2003). Strikingly, a more recent detailed analysis of the CD83 mRNA revealed that this transcript contains a novel cis-active RNA Digoxigenin-11-UTP mg in its coding region, termed the post-transcriptional regulatory element (PRE), which serves as HuR binding site (Prechtel et al. 2006). Furthermore, it has been shown that, upon binding of HuR to this CD83 RNA element, the HuR protein ligand ANP32B/APRIL is also recruited into this ribonucleoprotein (RNP) complex (Fries et al. 2007). ANP32B/APRIL belongs to a group of leucine-rich acidic nuclear phosphoproteins (ANP32a-h), which have been linked to various cellular processes, including the regulation of gene expression and cell signaling (reviewed in Matilla and Radrizzani 2005). With respect to the data reported here it is important to emphasize the fact that ANP32B/APRIL contains a nuclear export signal (NES) that allows the interaction with CRM1 (Brennan et al. 2000; Fries et al. 2007). Thus, HuR together with ANP32B/APRIL is capable to connect the CD83 mRNA with the CRM1 transport pathway. Obviously, our finding that CRM1 activity is fundamental to the maturation of immune-competent DC is in agreement with the aforementioned data. Particularly the further dissection of the post-transcriptional regulation of CD83 expression may provide novel target structures that not only indirectly interfere with CD83 translation, but may also provide new possibilities to develop advanced immune therapies, which are based on the modulation of DC activity. Clearly, the complete inhibition of an essential karyopherin, such as CRM1, will most likely induce undesired pleiotropic effects during long-term therapies. However, by targeting activities prior to CRM1-mediated translocation of a specific mRNA through the nuclear pore, one may achieve the required specificity. For example, it has been already shown that the mutation of the phosphor acceptor threonine244 in ANP32B/APRIL negatively interferes with CD83 expression (Fries et al. 2007). The subsequent identification of Casein Kinase 2 as the threonine244-specific kinase (Chemnitz et al. 2009) may not only provide a novel opportunity to suppress CD83 expression but may also allow the modulation of DC activity.
    Acknowledgements
    Introduction Nonmelanoma skin cancer (NMSC) is the most common cancer in fair skinned populations. Exposure to UV radiation, along with fair skin, immune status and HPV infection, are the greatest risk factors (Akgul et al., 2006a, Feltkamp et al., 2008). A link between HPV infections and the development of skin cancer was first discovered in patients with the rare autosomal recessive disorder epidermodysplasia verruciformis (EV). Among the 14 types of cutaneous HPVs found in skin tumors of EV patients, the beta genus HPV 5 and 8 are specifically linked to malignant lesions and actinic keratoses and have been classified as high risk types (Akgul et al., 2006a, Bouwes Bavinck et al., 2008, Dubina and Goldenberg, 2009, Feltkamp et al., 2008, zur Hausen, 2009). Although EV patients are rare, the incidence of beta genus HPV associated squamous cell carcinoma (SCC) is highly increased in immunocompromised patients with beta-HPV DNA being detected in up to 90% of skin cancers of these individuals (Akgul et al., 2006a).