Abstract
Karyopherin proteins mediate nucleocytoplasmic trafficking and are critical for protein and RNA subcellular localization. Recent studies suggest KPNA2 expression is induced in tumor cells and is strongly associated with prognosis, although the precise roles and mechanisms of KPNA2 overexpression in proliferative disorders have not been defined. We found that KPNA2 expression is induced in various proliferative disorders of the skin such as psoriasis, Bowen’s disease, actinic keratosis, squamous cell carcinoma, Paget’s disease, Merkel cell carcinoma, and mycosis fungoides. siRNA-mediated KPNA suppression revealed that KPNA2 is essential for significant suppression of HaCaT proliferation under starvation conditions. Ribosomal RNA transcription and protein synthesis were suppressed by starvation combined with knockdown of KPNA (including KPNA2) expression. KPNA2 localized to the nucleolus and interacted with proteins associated with mRNA processing, ribonucleoprotein complex biogenesis, chromatin modification, and transcription, as demonstrated by tandem affinity purification and mass spectrometry. KPNA2 may be an important promoter of ribosomal RNA and protein synthesis in tumor cells.
Highlights
Recent studies have defined the molecular mechanisms of nucleocytoplasmic signal transduction by karyopherins (KPNs), which function as receptors for various intracellular molecules and mediate nuclear import and export during interphase
This was the first report to show that KPNA2 is essential for cell growth in terms of rRNA and protein synthesis under starvation conditions
In the basal cells of psoriasis, KPNA2 expression was diffusely up-regulated in comparison to atopic dermatitis
Summary
Recent studies have defined the molecular mechanisms of nucleocytoplasmic signal transduction by karyopherins (KPNs), which function as receptors for various intracellular molecules and mediate nuclear import and export during interphase. KPNA2 expression in human epidermal keratinocytes, but not in human dermal fibroblasts, is differentially regulated by transforming growth factor (TGF)-b1 and interferon (IFN)-c, both of which are established modulators of epidermal proliferation and differentiation [4]. Karyopherin alphas mediate mitotic spindle assembly [7,8,9] and nuclear membrane formation [10]. KPNB1 is a global regulator of mitotic spindle assembly, centrosome dynamics, nuclear membrane formation, and nuclear pore complex assembly [11,12]. The precise roles and mechanisms of KPN overexpression in proliferative disorders have not been defined
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