Fuzzy Tandem Repeats Containing p53 Response Elements May Define Species-Specific p53 Target Genes

Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species

AFFINE for Enforcing Earlier Consideration of NFRs and Human Factors When Building Socio-Technical Systems Following Agile Methodologies

Nowadays, various user-centered and participatory design methodologies with different degree of agility are followed when building sophisticated socio-technical systems. Even when applying these methods, non-functional requirements (NFRs) are often considered too late in the development process and tension that may arise between users’ and developers’ needs remains mostly neglected. Furthermore, there is a conceptual lack of guidance and support for efficiently fulfilling NFRs in terms of software architecture in general. This paper aims at introducing the AFFINE framework simultaneously addressing these needs with (1) conceptually considering NFRs early in the development process, (2) explicitly balancing end-users’ with developers’ needs, and (3) a reference architecture providing support for NFRs. Constitutive requirements for AFFINE were gathered based on experiences from various projects on designing and implementing groupware systems

Towards Transparent Anonymity for User-controlled Servers Supporting Collaborative Scenarios

The increasing tendency of using user-controlled servers for supporting different scenarios from leisure and professional life raises new security challenges. Especially when those servers are used to support collaborative scenarios (e.g., communication and sharing with others), the requirement for anonymity at the network level should be supported in an efficient way. In this paper we present a specific communication scenario that could lead to link ability even though anonymous networks are used. The requirements gathering is based on realistic requirements from the EU FP7 di.me project requiring to empower lay end-users to collaborate with their contacts. Thereby anonymity at the network level also needs to be considered in order to disguise the physical location of the users and also of their server(s). We present an approach satisfying these anonymity requirements by means of a Tor based software component in order to overcome such privacy problems. First results are presented and the portability of the suggested solution for similar settings as well as future work directions are discussed

Tailoring Collaboration According Privacy Needs in Real-Identity Collaborative Systems

Nowadays, collaboration and social interaction among people become everyday activities in our evolving information age. In many learning platforms, collaborative platforms in the educational and industrial field or social networks like LinkedIn or Xing, users have to disclose private information and reveal their identities. Working with those systems allows them to create user profiles which could reveal more information about the user, than he wants to give. Furthermore, such environments may construct profiles about users’ interaction, which may be used for attacks; thus preserving privacy is an essential component of such environments. In this paper, a decentralized group-centric approach for tailoring collaboration according privacy needs is introduced. The main idea of our approach lays in its construction. In contrast to traditional collaboration environments with central hosting, our approach gives each group the whole responsibility of hosting the collaboration environment by using their own technical means. The feasibility of our approach is demonstrated through a lightweight ubiquitous collaboration platform. The experiences gathered are discussed

Mdm4 loss in mice expressing a p53 hypomorph alters tumor spectrum without improving survival

International audienceThe p53 pathway is inactivated in most human cancers, and its reactivation in tumors appears as a promising therapeutic strategy. Overexpression of Mdm4, a p53 negative regulator, occurs in a significant fraction of human cancers. Mouse models were used to evaluate the therapeutic potential of strategies against Mdm4, and encouraging results were obtained for tumor cells in which Mdm4 overexpression prevents wild-type p53 to exert its tumor suppressive functions. However, missense mutations in the p53 gene occur in about half of human cancers, and 15% of such mutations lead to the expression of a mutant protein that retains partial activity. In this report, we used mouse models to address the therapeutic potential of strategies against Mdm4 in tumors expressing an hypomorphic p53 mutant. We found that, in an Rb(+/-) background promoting pituitary and thyroid tumors, decreased Mdm4 levels improved the survival of mice expressing wild-type p53, but not that of mice expressing p53(ΔP), a p53 hypomorph lacking the proline-rich domain. Importantly, however, most Rb(+/-) p53(ΔP/ΔP) mice developped pituitary adenomas, but these tumors were rare in Rb(+/-) p53(ΔP/ΔP) Mdm4(-/-) animals, because Mdm4 loss led to increased p21 levels, a suppressor of pituitary tumor growth. On the contrary, Rb(+/-) p53(ΔP/ΔP) and Rb(+/-) p53(ΔP/ΔP) Mdm4(-/-) mice developped anaplastic thyroid carcinomas at equal frequencies. Importantly, wild-type p53 represses the Plk1 gene, which encodes a promising therapeutic target in anaplastic thyroid carcinomas, and this repression is improved when Mdm4 levels are decreased. On the opposite, p53(ΔP) is a mediocre transcriptional repressor that is not improved by Mdm4 loss. In sum, depending on the tumor type, strategies against Mdm4 that work in cells expressing wild-type p53 may not work in cells expressing an hypomorphic p53. Furthermore, p53-mediated transcriptional repression should be considered when evaluating strategies to reactivate p53 in tumors