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p8 is a stress gene whose activity is necessary for tumor development and progression. The acquisition of invasive properties by transformed cells is a key event in tumor development. In order to establish whether p8 is involved or not in this phenomenon, we assessed the capacity of p8 at influencing cell adhesion, migration, invasion, and tumorigenesis of pancreatic cancer cells. p8 expression was knocked down by a small interfering RNA (siRNA) in pancreatic cancer-derived Panc-1 and MiaPaCa-2 cells and subsequent changes in cell adhesion, migration, invasion, and tumorigenesis were assessed. Influence of p8 silencing on gene expression was analyzed using cDNA microarrays. The influence of inhibiting CDC42, one of the genes most over-expressed in p8-silenced cells, on the changes observed in p8-silenced cells was also evaluated. Finally, the tumorigenic capacities of Panc-1 cells transfected with control siRNA or p8 siRNA were compared by assessing their ability to form colonies in soft agar and to grow as xenografts in nude mice. Knocking-down p8 in pancreatic cancer cells in vitro decreased migration and invasion while increasing cell adhesion; over-expression produced the opposite effect. Knocking down CDC42 reversed almost completely the effects of silencing p8 in vitro. Finally, cells transfected with p8 siRNA were almost unable to form colonies in soft agar. In addition, p8-deficient Panc-1 cells did not develop tumors when injected subcutaneously in nude mice. In conclusion, p8 expression controls pancreatic cancer cell migration, invasion and adhesion, three processes required for metastasis, at least in part, through CDC42, a major regulator of cytoskeleton organization., (Copyright © 2011 Wiley-Liss, Inc.)

Nupr1 is a small, highly basic and loosely folded multifunctional protein whose expression is induced by several stresses. Its relation to cancer was first suggested by its overexpression in several human malignancies and the association of its expression with breast cancer metastasis. Accordingly, Nupr1 is structurally related to the high-mobility group (HMG) of transcriptional regulators, which play a key role in the stress response and in cancer progression. Nupr1 interacts with numerous partners to regulate cell cycle, programmed cell death, autophagy, chromatin accessibility, and transcription, and its expression is required for regulation of TGFβ activity. Pleiotropic functions accomplished by Nupr1 depend on its molecular partners, its location into the cell, its expression level and on the cell-type. Nupr1 might be a new drug-targetable protein whose blockade would prevent cancer progression and metastasis development., (Copyright © 2010 Wiley-Liss, Inc.)

The stress protein p8 is a small, highly basic, unfolded, and multifunctional protein. We have previously shown that most of its functions are exerted through interactions with other proteins, whose activities are thereby enhanced or repressed. In this work we describe another example of such mechanism, by which p8 binds and negatively regulates MSL1, a histone acetyl transferase (HAT)-associated protein, which in turn binds the DNA-damage-associated 53BP1 protein to facilitate DNA repair following DNA gamma-irradiation. Contrary to the HAT-associated activity, MSL1-dependent DNA-repair activity is almost completely dependent on 53BP1 expression. The picture that has emerged from our findings is that 53BP1 could be a scaffold that gets the HAT MSL1-dependent DNA-repair activity to the sites of DNA damage. Finally, we also found that, although p8 expression is transiently activated after gamma-irradiation, it is eventually submitted to sustained down-regulation, presumably to allow development of MSL1-associated DNA-repair activity. We conclude that interaction of MSL1 with 53BP1 brings MSL1-dependent HAT activity to the vicinity of damaged DNA. MSL1-dependent HAT activity, which is negatively regulated by the stress protein p8, induces chromatin remodeling and relaxation allowing access to DNA of the repair machinery.