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SOX2 regulates proliferation through VRK1 promoter activation

AuthorsMoura, David S.; Marín-Royo, Gema; Lazo, Pedro A.
Issue Date2015
Citation15th ASEICA International Congress (2015)
Abstract[Introduction]: Cell proliferation and cell differentiation are two distinct processes occurring at different stages of the cell life. Nonetheless, the regulatory mechanisms involved in the switch from proliferation to differentiation and the role and fate of proliferation-related proteins are yet to be fully understood. Sox2, a member of the SRY-related HMG-box family of transcriptional factors, is a core regulator of cell pluripotency and cell proliferation, survival and differentiation. Moreover, Sox2 may act as a cancer initiating gene in poorly differentiated or undifferentiated tumors, since these types of cancers have been characterized by many phenotypic traits similar to undifferentiated embryonic stem cells. Sox2 activates the promoter of yclin D1. In turn, VRK1 (Vaccinia-related Kinase-1) is a serine-threonine kinase ubiquitously expressed, with higher expression in highly-proliferative tissues, such as tumours. Thus, based on VRK1 features and expression, this kinase was related with the regulation of cell cycle and cell proliferation. Nowadays, it is known that VRK1 takes part in the correct progression of cell cycle through transcriptional factors regulation, regulation of proliferative proteins like Cyclin D1, modulation of p53 levels, nuclear envelope assembly and chromatin condensation. [Objectives]: We hypothesize that VRK1 regulates and is regulated Sox2. This regulation is important to maintain cell proliferation. Besides, we hypothesize that VRK1 could act as a transcriptional partner for Sox2 on the activation of CCND1 gene.
[Methods]: The levels and co-localization of VRK1 and Sox2 were analyzed by immunofluorescence (IF) and immunohistochemistry. Interaction between VRK1 and Sox2 was assessed by reciprocal immunoprecipitations in Ntera-2 cells and MDA-MB-231 cells. Moreover, the effect of cell differentiation on VRK1 and Sox2 levels was studied by qRT-PCR, Western blot and IF. The activation of VRK1 promoter by Sox2 overexpression was assessed by luciferase assays, qRT-PCR, Western blot and IF. Moreover, the cooperation between VRK1 and Sox2 on CCND1 gene activation was evaluated by luciferase assays. [Results]: Here, we showed that VRK1 and Sox2 interact and co-localize in Ntera-2 and MDA-MB-231 and, in undifferentiated layers of stratified squamous epithelium. Sox2 overexpression induces an increase in the VRK1 promoter activity, alongside with an increment on VRK RNA and protein levels. On the other hand, down-regulation of VRK1 leads to an increase in Sox2 RNA and protein levels, while the overexpression has the opposite effect. Also VRK1 and Sox2 can activate, by themselves and in cooperation, expression of the CCND1 (cyclinD1) gene. This effect of VRK1 and Sox2 is mediated by the proximal promoter of CCND1. After induction of cell differentiation with retinoic acid, both Sox2 and VRK1 are downregulated and they are absent in terminally differentiated epithelial cells. [Conclusions]: VRK1 regulates and is regulated by Sox2. Additionally, VRK1 and Sox2 cooperate on the activation of CCND1 gene.
DescriptionResumen del trabajo presentado al 15th ASEICA International Congress, celebrado en Sevilla (España) del 21 al 23 de octubre de 2015.
Appears in Collections:(IBMCC) Comunicaciones congresos
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