In a subset of preinvasive lesions, and are further lost in cancer and perineural invasion lesions. The rare tumor-associated primary cilia are shorter in preinvasive and invasive prostate cancer, which may reflect dysfunction. High nuclear ��-catenin correlates with low primary cilia frequency in normal prostate tissue. In future work, it will be important to determine if primary cilia loss is causal to tumor formation. Ubiquitylation has been well characterized to regulate vital cellular processes mainly through proteasome-dependent degradation of polyubiquitinated substrates; however, proteolysisindependent roles of ubiquitylation have emerged as key mechanisms in various signaling cascades. Typically, polyubiquitin chains that target proteins for degradation by the proteasome are linked through K48 of ubiquitin. On the contrary, K63-linked polyubiquitin chains play multiple roles in kinase activation, DNA repair and intracellular trafficking via proteasome-independent mechanisms. A frameshift mutation of ubiquitin called ubiquitin +1 was found in the aging and Alzheimer’s disease brains. UBB +1 is generated by transcriptional dinucleotide deletion within the mRNA resulting in a 19-amino acid extension at the Cterminus of ubiquitin. This mutant ubiquitin cannot link to substrates targeted for proteasomal degradation, but is ubiquitylated to form a polyubiquitin chain. Ubiquitylated UBB +1 is refractory to deubiquitination, resulting in dominant inhibition of the ubiquitin-proteasome system. Recent evidences have revealed that UBB +1 is detected as pathological hallmarks in various neurodegenerative diseases and exacerbates the proteasomal dysfunction and deposition of toxic proteins. It was also reported that UBB +1 exerts a neurotoxic effect by suppressing proteasome-dependent proteolysis in neurons. Astrocytes, the most abundant glial cells in the central nervous system, play important roles in maintaining the homeostatic environment and immune regulation, producing a repertoire of inflammatory mediators including chemokines, cytokines and adhesion molecules. Interleukin-1b and tumor necrosis factor-a serve as major regulators of immune and inflammatory responses in the CNS, and elevated expression of these cytokines occurs in injury, infection, stroke, inflammation and degenerative disorders such as AD. These proinflammatory cytokines induce 
expression of multiple genes associated with inflammation by human astrocytes. In response to IL-1b and TNF-a, ubiquitylation-dependent activation of TNFassociated factor 6 and TRAF2 complexes leads to activation of TGF-b-activated kinase 1 which activates nuclear factor kappa B and c-Jun NH2-terminus kinase pathways. In this study, we investigated the effect of UBB +1 on proinflammatory signaling such as IL-1b and TNF-a in human astrocytes, and its functional relevance of ubiquitindependent kinase activation.