The structural characteristics of the three nuclear phosphoproteins of the high mobility group A family are outlined and related to their participation in chromatin structure alteration in many biological processes such as gene expression, neoplastic transformation, differentiation, and apoptosis. The elevated expression of these proteins in tumor cells and their post-translational modifications, such as phosphorylation, acetylation and methylation, are discussed and suggested as suitable targets for cancer chemotherapy.

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Orexins are neuro-modulatory peptides involved in the control of diverse physiological functions through interaction with two receptors, orexin-1 (OX1R) and orexin-2 (OX2R). Recent evidence in pre-clinical models points toward a putative dichotomic role of the two receptors, with OX2R predominantly involved in the regulation of the sleep/wake cycle and arousal, and the OX1R being more specifically involved in reward processing and motivated behaviour. However, the specific neural substrates underlying these distinct processes in the rat brain remain to be elucidated. Here we used functional magnetic resonance imaging (fMRI) in the rat to map the modulatory effect of selective OXR blockade on the functional response produced by D-amphetamine, a psychostimulant and arousing drug that stimulates orexigenic activity. OXR blockade was produced by GSK1059865 and JNJ1037049, two novel OX1R and OX2R antagonists with unprecedented selectivity at the counter receptor type. Both drugs inhibited the functional response to D-amphetamine albeit with distinct neuroanatomical patterns: GSK1059865 focally modulated functional responses in striatal terminals, whereas JNJ1037049 induced a widespread pattern of attenuation characterised by a prominent cortical involvement. At the same doses tested in the fMRI study, JNJ1037049 exhibited robust hypnotic properties, while GSK1059865 failed to display significant sleep-promoting effects, but significantly reduced drug-seeking behaviour in cocaine-induced conditioned place preference. Collectively, these findings highlight an essential contribution of the OX2R in modulating cortical activity and arousal, an effect that is consistent with the robust hypnotic effect exhibited by JNJ1037049. The subcortical and striatal pattern observed with GSK1059865 represent a possible neurofunctional correlate for the modulatory role of OX1R in controlling reward-processing and goal-oriented behaviours in the rat.

The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120 E4F , interfering with p120 E4F binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.HMGA2 belongs, together with HMGA1a and HMGA1b, to the HMGA family of nuclear proteins, whose expression has functional implications in the pathogenesis of several human tumors (2,20,47,50). A strong association between the expression of these proteins and the transformed phenotype has been observed since they were first described, in transformed rat thyroid cells (24,25), and was later found in several human neoplasias (e.g., colon, prostate, cervical, and thyroid carcinomas) (4, 10, 17, 51). Their expression is very low, if not absent, in adult tissues and is restricted to embryogenesis (11,28,32,55).The first evidence of a direct role played by these factors in tumorigenesis came from transfection of an antisense construct for HMGA2 in normal rat thyroid cells that prevented the neoplastic transformation induced by myeloproliferative sarcoma virus and kirsten murine sarcoma virus (7). More recently, the increased expression of all three HMGA family members was shown to lead to transformation with anchorageindependent cell growth (53, 54), and the overexpression of HMGA1 was also shown to promote tumor progression in human breast epithelial cells (41). Of additional interest, rearrangements of the HMGA2 gene, resulting in the loss of the acidic C-terminal tail, have been frequently detected in benign human tumors of mesenchimal origin (50). Indeed, transgenic mice expressing the truncated HMGA2 protein develop tumors such as lipomas and natural killer lymphomas (1, 3, 6, 18), while mice expressing wild-type HMGA2 develop pituitary adenomas (19).Despite this evidence, the molecular events and the precise role played by HMGA2 in cell proliferation and tumorigenesis still need to be defined.HMGA proteins contain about 100 amino acid residues and have three DNA-binding domains which have been named AT hooks because of their ability to interact with the narrow minor groove of AT-rich DNA sequences (42). These nuclear proteins, by binding to DNA and/or to transcription factors, can organi...

Drugs of abuse, including, nicotine have been shown to enhance brain reward functions in the mesocortico-limbic dopamine (DA) system in general, and the nucleus accumbens in particular. The latter occupies a prominent position in the ventral striatum and expresses a high density of DA D 3 receptors. As such, the present study aimed at investigating the effect of the selective D 3 receptor antagonist SB-277011-A on both the stable maintenance of intravenous nicotine self-administration and nicotine-triggered relapse to nicotine-seeking behavior in the rat. SB-277011-A (3-10 mg/kg i.p.) significantly reduced reinstatement of nicotine-seeking behavior without affecting nicotine self-administration per se. These results suggest that DA D 3 receptors are involved in the reinstatement of nicotine-seeking behavior independently of any interaction with the primary reinforcing effects of nicotine itself. These findings point toward the potential use of selective DA D 3 receptor antagonists for the pharmacotherapeutic management of relapse to drug-seeking behaviors.