The c-jun proto-oncogene encodes a component of the mitogen-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and G 1 -to-S-phase progression. Here we report that fibroblasts derived from c-jun −/− mouse fetuses exhibit a severe proliferation defect and undergo a prolonged crisis before spontaneous immortalization. The cyclin D1-and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G 1 -to-S-phase progression. The control of mammalian cell proliferation by mitogens occurs largely during the G 1 phase of the cell cycle. During this period, extracellular signals are transduced by cytoplasmic signaling cascades to the nuclear cell cycle clock, where a decision is made between cell cycle progression and quiescence (Sherr 1994(Sherr , 1996. Among the earliest responses to mitogenic signaling is activation of transcription factors such as c-Jun, a subunit of activator protein 1 (AP-1) (Angel and Karin 1991). Transcriptional activation of yet-to-be-identified target genes by c-Jun and other immediate early transcription factors is thought to be essential for mitogen-induced progression through the cell cycle. A causal role of c-Jun in promoting cell division was indeed suggested by studies using microinjection of neutralizing antibodies or antisense RNA, which cause a partial G 0 arrest and block entry into S phase (Kovary and Bravo 1991;Riabowol et al. 1992;Smith and Prochownik 1992). Conversely, cell cycle distribution in cells overexpressing c-Jun is shifted toward S phase (Pfarr et al. 1994). c-Jun can act as an oncogene when mutated or expressed in a deregulated way, an ability that is shared by several cell cycle proteins promoting cell division such as cylin D1, cyclindependent kinase-4 (CDK4), c-Myc, and possibly E2F (Angel and Karin 1991; Sherr 1996;Weinberg 1996). In addition, c-Jun is involved in the control of apoptosis (Ham et al. 1995;Verheij et al. 1996;Bossy-Wetzel et al. 1997) and differentiation (Lord et al. 1993;Bohmann et al. 1994;Szabo et al. 1994;Patel and Sytkowski 1995). Although the mitogenic signaling pathways acting upstream of c-Jun are reasonably well understood, as is the basic cell cycle machinery, the connections between the two are still unclear (Cano and Mahadevan 1995;Karin and Hunter 1995).The core cell cycle clock itself operates by sequential activation and inactivation of a number of protein kinase complexes known as CDKs Sherr 1996). In G 1 , these kinases consist of cyclin D1, D2, or D3 associated with CDK4 or CDK6 and cyclin E-CDK2 and phosphorylate, among others, the retinoblastoma protein (pRb) (Weinberg 1995

Background Acute pancreatitis is a painful inflammatory disorder known to occur in children. Recent reports, primarily on the basis of adult data, have suggested an increasing incidence. However, pediatric studies are limited. Objective The study was performed to examine the frequency of acute pancreatitis in a pediatric population from 1994 to 2007 and to characterize etiologies by age subsets. Patients and Methods In this retrospective study, cases of pancreatitis were identified by ICD-9 codes and subjected to inclusion criteria. Results Two hundred and seventy-one cases of pancreatitis met inclusion criteria. Mean age of the subjects was 13.1 ± 5.6 years. The recurrence rate was 15.3%. Biliary disease was the most common etiology (32.6%). Acute pancreatitis cases evaluated at a single tertiary care center increased 53% between 1995 to 2000 and 2001 to 2006 (P <0.02). However, when cases were normalized by all annual pediatric emergency department visits for all medical reasons, the increase was reduced to 22% and lost statistical significance (P = 0.16). The rise was not associated with a change in etiologies or body mass index (BMI). Conclusions This is the first report demonstrating that an increase in pediatric pancreatitis may in part be due to growing referrals to tertiary care centers. The data on etiologies, particularly with regard to differing ages, may be helpful in managing children who present with acute pancreatitis.

Hepatocyte nuclear factor 1 (HNF-1) is a transcriptional regulatory protein possibly involved in the activation of many liver-specifically expressed genes. HNF-1 mRNA is restricted to a small number of tissues, suggesting that the HNF-1 gene itself is regulated at the transcriptional level. We have isolated and characterized the promoter region of this gene and have determined its transcriptional potential in several cell types by cell-free transcription and transient transfection experiments. In in vitro transcription assays, an HNF-1 promoter is active in nuclear extracts from liver and kidney, two tissues that contain HNF-1, but silent in nuclear extracts from spleen and lung, which are devoid of this transcription factor. Likewise, in transfection experiments, HNF-1 promoter-chloramphenicol acetyltransferase (CAT) fusion genes are expressed in Hep G2 cells, which express HNF-1, but not in mouse L cells or Hela cells, which do not express HNF-1. In both cell-free transcription and transient transfection assays, a relatively short promoter segment located between positions -82 and -40 is necessary and sufficient to direct cell type-specific HNF-1 transcription. This region contains a single site for a DNA-binding protein that has been tentatively identified as hepatocyte nuclear factor 4, a member of the steroid hormone receptor family.

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Traumatic brain injury (TBI) negatively impacts long-term survival. However, little is known about the likelihood of death within the first year following hospital discharge. This study examined mortality among a representative sample of 3679 persons within 1 year of being discharged from any of 62 acute care hospitals in South Carolina following TBI and identified the factors associated with early death using a multivariable Cox proportional hazards model. The mortality experience of the cohort was also compared with that of the general population by using standardized mortality ratios for selected causes of death by age, adjusted for race and sex.