JAB1 (Jun activation domain-binding protein-1) has previously been described as a coactivator of AP1 transcription factor. We show here, by yeast and mammalian two-hybrid analyses and by pull-down experiments, that JAB1 also interacts with both the progesterone receptor (PR) and the steroid receptor coactivator 1 (SRC-1) and that it stabilizes PR-SRC-1 complexes. We also show that JAB1 potentiates the activity of a variety of transcription factors known to associate with SRC-1 (nuclear receptors, activator protein-1, and nuclear factor B). This occurs without any modification of PR or SRC-1 concentration. JAB1 is a subunit of a large multiprotein complex that has been called the COP9 signalosome. The latter is present in plant and animal cells and has been shown to be involved in a variety of cellular mechanisms including transcription regulation, cell cycle control, and phosphorylation cascades. We now show that it is also involved in the mechanisms of action of nuclear receptors and of their coactivators.JAB1 (Jun activation domain-binding protein-1) was initially isolated by a two-hybrid screen (1) using the c-Jun Nterminal activation domain as a bait. It was shown that JAB1 potentiates target gene transcription activation by AP1 proteins (especially c-Jun and JunD) (1). This initial study also pointed to the sequence homology between JAB1 and the yeast protein Pad-1. The latter has been demonstrated to be necessary for the transcriptional activity of Pap-1, the yeast equivalent of c-Jun (1, 2). Furthermore it was shown that JAB1 could functionally replace Pad-1 in yeast. Thus JAB1 and Pad-1 appeared to play similar roles in mammalian and yeast cells, respectively. However, recent studies have uncovered the true human homolog of Pad-1, which has been called POH-1. Both Pad-1 and POH-1 are components of the 26 S proteasome (3, 4).On the contrary JAB1 is not found in the proteasome but has very recently been shown to be a subunit of a different multiprotein complex that has been called the signalosome (or COP9 signalosome). This complex contains several proteins with sequence homologies to proteins present in the regulatory 19 S subunit of the 26 S proteasome (5-7). It has been proposed that the latter and the signalosome have a common evolutionary origin but have diverged to assume different cellular functions.Moreover recent studies have shown an interaction of Fos/ Jun with SRC-1. The latter potentiates AP1 1 -mediated gene transactivation (8). SRC-1, also called p160 and ERAP160 (9 -12) is a member of the large family of nuclear receptor coactivators including SRC-2 (also called TIF2 and GRIP1) (13, 14), SRC-3 (also called TRAM1, ACTR, AIB1, RAC3, and p/CIP) (15-19), and ARA-70 (androgen receptor-associated protein) (20). These proteins form complexes with nuclear receptors and CBP or p300 (12,16,19,(21)(22)(23)(24). The latter recruit into transcription complexes histone acetylases such as p300/CBP-associated factor (16,25,26). Coactivators CBP and p300 also have intrinsic histone acetylase activity. Histo...

Modulators of cofactor recruitment by nuclear receptors are expected to play an important role in the coordination of hormone-induced transactivation processes. To identify such factors interacting with the N-terminal domain (NTD) of the progesterone receptor (PR), we used this domain as bait in the yeast Sos-Ras two-hybrid system. cDNAs encoding the C-terminal MYST (MOZ-Ybf2/Sas3-Sas2-Tip60 acetyltransferases) domain of HBO1 [histone acetyltransferase binding to the origin recognition complex (ORC) 1 subunit], a member of the MYST acetylase family, were thus selected from a human testis cDNA library. In transiently transfected CV1 cells, the wild-type HBO1 [611 amino acids (aa)] enhanced transcription mediated by steroid receptors, notably PR, mineralocorticoid receptor, and glucocorticoid receptor, and strongly induced PR and estrogen receptor coactivation by steroid receptor coactivator 1a (SRC-1a). As assessed by two-hybrid and glutathione-S-transferase pull-down assays, the HBO1 MYST acetylase domain (aa 340-611) interacts mainly with the NTD, and also contacts the DNA-binding domain and the hinge domains of hormone-bound PR. The HBO1 N-terminal region (aa 1-340) associates additionally with PR ligand-binding domain (LBD). HBO1 was found also to interact through its NTD with SRC-1a in the absence of steroid receptor. The latter coassociation enhanced specifically activation function 2 activation function encompassed in the LBD. Conversely, the MYST acetylase domain specifically enhanced SRC-1 coupling with PR NTD, through a hormone-dependent mechanism. In human embryonic kidney 293 cells expressing human PRA or PRB, HBO1 raised selectively an SRC-1-dependent response of PRB but failed to regulate PRA activity. We show that HBO1 acts through modification of an LBD-controlled structure present in the N terminus of PRB leading to the modulation of SRC-1 functional coupling with activation function 3-mediated transcription. Importantly, real-time RT-PCR analysis also revealed that HBO1 enhanced SRC-1 coactivation of PR-dependent transcription of human endogenous genes such as alpha-6 integrin and 11beta-hydroxydehydrogenase 2 but not that of amphiregulin. Immunofluorescence and confocal microscopy of human embryonic kidney-PRB cells demonstrated that the hormone induces the colocalization of HBO1 with PR-SRC-1 complex into nuclear speckles characteristic of PR-mediated chromatin remodeling. Our results suggest that HBO1 might play an important physiological role in human PR signaling.

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Intravascular lymphoma is an extremely rare, disseminated, and aggressive extranodal CD20+ non-Hodgkin's lymphoma characterized by the presence of lymphoma cells only in the lumina of small vessels. We report a 72-year-old woman with a diagnosis of intravascular lymphoma presented with splenomegaly and leukemic appearance in the peripheral blood smear. Her clinical course was rapidly deteriorated before the initiation of specific chemotherapy and finally died due to multiorgan insufficiency. Bone marrow biopsy revealed a characteristic infiltration of CD5, CD10 B-cell lymphoma. To our knowledge, this is the first reported case of a CD5, CD10 intravascular B-cell lymphoma with leukemic presentation in peripheral blood with multiple cytogenetic aberrations.

INTRODUCTION:Various pathways, such as personperson, fecal-oral, and oral-oral transmission, play a role in transmission of Helicobacter pylori infection. It can be transferred from mother to infant in either the perinatal or postnatal periods. OBJECTIVE: The aim of this prospective study was to determine the course of H pylori infection in motherinfant pairs in early years of life. METHODS: Forty-eight mother-child pairs were followed for 12 months. H pylori and hepatitis A virus immunoglobulin G levels were measured in maternal sera, infant sera, and breast-milk samples at birth and in breast-milk samples and infant sera at follow-up visits. RESULTS: At birth, the seropositivity for H pylori was 81.25% and hepatitis A was 68.75% in breast milk and 95.8% in maternal and infant sera for both microorganisms. Although there was a decrease in seropositivities for both agents in both infant sera and breast milk at the age of 9 months, an increase was observed in the twelfth month. CONCLUSIONS: High seroprevalence rates of H pylori and hepatitis A virus and similar monthly changes in seroprevalence could be indicators of the same transmission routes. IMPACT OF ZINC SUPPLEMENTATION ON GROWTH: A DOUBLE-BLIND, RANDOMIZED TRIAL AMONG URBAN IRANIAN SCHOOLCHILDREN Submitted by Nahid MasoodpoorNahideh Masoodpoor, R. Darakshan Rafsanjan Medical Hospital, Rafsanjan, Iran INTRODUCTION:The first study that linked zinc and growth was carried out in Iran and Egypt almost 3 decades ago. At the time, the circumstances leading to growth impairment secondary to zinc deficiency were believed to be unique in less developed countries. Multiple studies have been carried out to assess the effect of zinc supplementation on children's growth. The results of these studies have been inconsistent. OBJECTIVE: The aim of this study was to investigate the impact of zinc supplementation on growth (weight and height) among schoolchildren who were underweight or had stunted growth. METHODS: Our study was a randomized, double-blind, placebo-controlled trial of 90 Iranian urban schoolchildren (50 boys and 40 girls; 7-12 years old) who were underweight or stunted and were supplemented with 10 mg of zinc or placebo on school days for 6 months. Variables were weight and height.RESULTS: Significant effects on weight gain (2.037 Ϯ 1.240 vs 1.55 Ϯ 0.64 kg; P ϭ .0167) and height (2.030 Ϯ 1.003 vs 1.403 Ϯ 0.521 cm; P ϭ .0002) in the children after zinc supplementation versus placebo administration, respectively, were seen over the 6-month period. CONCLUSIONS: On the basis of this study, zinc supplementation improved growth in underweight or stunted children and should be considered for populations at risk for zinc deficiency, especially where there are elevated rates of underweight or stunting. In this study, we attempted to estimate the incidence and clinical features of TEL/AML1 ϩ ALL for the first time in a representative cohort of Greek pediatric patients. METHODS: One hundred twenty children (Ͻ16 years old) diagnosed with ALL (107 of B-cell origin, 13 of...

The value and exact type of intensive chemotherapy of unselected elderly AML patients in terms of overall survival (OS) and quality of life remains controversial. The lack of large randomized trials comparing intensive to low dose treatment or to just supportive care as well as the selection bias observed in smaller studies in AML patients over 60 years contribute significantly to the clinical dilemma. Despite recent improvements in supportive measures during cytotoxic therapy, elderly AML patients continue to exhibit lower remission rates, higher toxicity, more relapses and eventually a worse survival. The present analysis evaluates in a retrospective manner the outcome of 39 homogeneously treated AML patients >60yrs during a period of 44 months (Nov 2001 to Aug 2005). The protocol schedule included an initial course of mitoxantrone + cytarabine 3+5 (12mg/m2/d and 100mg/m2 q12h respectively) followed by a second abbreviated course of mitoxantrone + cytarabine 2+5, followed by a final course of idarubicin + cytarabine + thioguanine 2+7+7 (10mg/m2/d, 100mg/m2 q12h and 100mg/m2/d respectively). G-CSF at 5μg/Kg was added to all courses to accelerate hematopoietic recovery. Our patient population consisted of 22 cases of de novo AML and 17 cases of secondary AML (MDS 16, NHL 1) classified according to FAB as follows: M0 (5), M1 (4), M2 (19), M4 (3), M5 (2), M6 (5), hybrid-leukemia (1). Their median age was 70 yrs (range 63–80 yrs) and M/F ratio was 27/12. Cytogenetic analysis was performed in 33/39 cases: 6/33 cases failed to produce metaphases, 20/33 cases revealed standard risk abnormalities (seventeen normal karyotype, three trisomy 8) and 7/33 cases had poor risk abnormalities by MRC cytogenetic criteria. Leukocytosis >50X109/L was noted in 6/39 and leukopenia<5X109/L was noted in 19/39 patients. After a median observation period of 9 months (range 1–40) the following results are available: 19/39 (48,7%) patients entered CR (13 de novo, 7 secondary) post-course 2 and their median OS is 15,5 months (range 2–40). An additional 6/39 (15,3%) cases returned to a myelodysplastic phase without excess of blasts achieving thus partial hematological remission. The remaining 14/39 (35,8%) patients proved primary resistant and deceased after a median of 2,5 months (range 1–20) with one resistant patient surviving 20 months with on-going disease. Within the group of remitters 3/19 deceased from complications (MI, fungal infection, sepsis) before the next chemotherapy course. The remaining 11/19 remitters relapsed after a median of 7,5 months (range 1–30); nine of them deceased and two are alive as a result of salvage treatment. Finally 5/19 cases remain alive and disease-free (two interrupted after the second course). Conclusion: Combination chemotherapy with mitoxantrone and cytarabine is well-tolerated and reasonably effective in elderly AML patients fit enough to undergo chemotherapy regardless of karyotype and antecedent blood dyscrasia. With a total response rate of 64% (CR+PR) and an induction death rate of 5,1% (2/39), the current schedule deserves further evaluation in a larger AML population. Furthermore, our data validate the improvement in survival of those patients achieving CR as suggested by other studies.