Rel/NF-kB transcription factors are key regulators of immune, in¯ammatory and acute phase responses and are also implicated in the control of cell proliferation and apoptosis. Remarkable progress has been made in understanding the signal transduction pathways that lead to the activation of Rel/NF-kB factors and the consequent induction of gene expression. Evidence linking deregulated Rel/NF-kB activity to oncogenesis in mammalian systems has emerged in recent years, consistent with the acute oncogenicity of the viral oncoprotein v-Rel in animal models. Chromosomal ampli®cation, overexpression and rearrangement of genes coding for Rel/NF-kB factors have been noted in many human hematopoietic and solid tumors. Persistent nuclear NF-kB activity was also described in several human cancer cell types, as a result of constitutive activation of upstream signaling kinases or mutations inactivating inhibitory IkB subunits. Studies point to a correlation between the activation of cellular gene expression by Rel/NF-kB factors and their participation in the malignant process. Experiments implicating NFkB in the control of the apoptotic response also support a role in oncogenesis and in the resistance of tumor cells to chemotherapy. This review focuses on the status of the rel, nfkb and ikb genes and their activity in human tumors and their association with the onset or progression of malignancies.

Most living organisms show circadian (ϳ24 h) rhythms in physiology and behavior. These oscillations are generated by endogenous circadian clocks, present in virtually all cells where they control key biological processes. Although circadian gating of mitosis has been reported for many years in some peripheral tissues, the underlying molecular mechanisms have remained poorly understood. Here we show that the cell cycle inhibitor p21 WAF1/CIP1 is rhythmically expressed in mouse peripheral organs. This rhythmic pattern of mRNA and protein expression was recapitulated in vitro in serum-shocked differentiated skeletal muscle cells. p21 WAF1/CIP1 circadian expression is dramatically increased and no longer rhythmic in clock-deficient Bmal1 ؊/؊ knock-out mice. Biochemical and genetic data show that oscillation of p21 WAF1/CIP1 gene transcription is regulated by the antagonistic activities of the orphan nuclear receptors REV-ERB␣/␤ and ROR␣4/␥, which are core clock regulators. Importantly, p21 WAF1/CIP1 overexpressing Bmal1 ؊/؊ primary hepatocytes exhibit a decreased proliferation rate. This phenotype could be reversed using small interfering RNA-mediated knockdown of p21 WAF1/CIP1 . These data establish a novel molecular link between clock and cell cycle genes and suggest that the G 1 progression phase is a target of the circadian clock during liver cell proliferation.Many physiological and behavioral processes display daynight oscillations in most organisms including mammals. These biological rhythms are controlled by endogenous selfsustained circadian (ϳ24 h) oscillators that operate not only in the central clock located in the suprachiasmatic nuclei of the hypothalamus but also in virtually all peripheral cells. Light is the main synchronizer of the central clock, which in turn coordinates the phases of peripheral oscillators regulating specific physiological outputs. Forward genetics and biochemical approaches have established the molecular basis underlying circadian oscillations in mammalian tissues (1-4). This mechanism involves complex interlocked positive and negative transcriptional/posttranslational feedback loops between the clock genes Clock, Bmal1, Per1, Per2, Cry1, and Cry2 and their protein products. The robustness of the oscillations is ensured by additional regulators such as the REV-ERB␣ (NR1D1) and ROR␣ (NR1F1) orphan nuclear receptors (5, 6). Furthermore, extensive multilevel posttranslational regulation of various clock components has also been shown to play an important role in the molecular clock mechanism (7).There are substantial evidences that progression through the cell cycle occurs at specific times of the day/night cycle, suggesting that a function of the circadian clock system is to control this fundamental process. Notably, after the initial observation almost 40 years ago that cell division of the unicellular algae Euglena was controlled by an endogenous clock (8), numerous studies have shown a circadian variation of the proliferative activity in mammalian tissues such as the epithelia ...

Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.

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