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T cell receptor (TCR) beta chain allelic exclusion occurs at the thymocyte CD4- 8- (double-negative, or DN) to CD4+ 8+ (double-positive, or DP) transition, concurrently with differentiation and cellular expansion, and is imposed by a negative feedback loop in which a product of the first rearranged TCRbeta allele arrests further recombination in the TCRbeta locus. All of the major events associated with the development of DP cells can be induced by the introduction of TCRbeta or activated Lck transgenes. Here, we present evidence that the signaling pathways that promote thymocyte differentiation and expansion of RAG-deficient DN cells but not those that suppress rearrangements of endogenous TCRbeta genes in normal DN cells are engaged by activated Ras. We propose that TCRbeta allelic exclusion is mediated by effector pathways downstream of Lck but independent of Ras.

The transcription factor hXBP-1 belongs to the family of basic region/leucine zipper (bZIP) proteins and interacts with the cAMP responsive element (CRE) of the major histocompatibility complex (MHC) class II A alpha, DR alpha and DP beta genes. However, the developmental expression of hXBP-1 as revealed by in situ hybridization in mouse embryos, has suggested that it interacts with the promoter of additional genes. To identify other potential target genes of this factor, we performed binding site selection experiments with recombinant hXBP-1 protein. The results indicated that hXBP-1 binds preferably to the CRE-like element GAT-GACGTG(T/G)NNN(A/T)T, wherein the core sequence ACGT is highly conserved, and that it also binds to some TPA response elements (TRE). hXBP-1 can transactivate multimers of the target sequences to which it binds in COS cells, and the level of transactivation directly correlates with the extent of binding as observed in gel retardation experiments. One target sequence that is strongly bound by hXBP-1 is the 21 bp repeat in the HTLV-1 LTR, and we demonstrate here that hXBP-1 can transactivate the HTLV-1 LTR. Further, the transactivation domain of hXBP-1 encompasses a large C-terminal region of the protein, containing domains rich in glutamine, serine and threonine, and proline and glutamine residues, as shown in transient transfection experiments using hXBP-1-GAL4 fusion proteins and a reporter gene under the control of GAL4-binding sites.

In hyperandrogenic women, several phenotypes may be observed. This includes women with classic polycystic ovary syndrome (C-PCOS), those with ovulatory (OV) PCOS, and women with idiopathic hyperandrogenism (IHA), which occurs in women with normal ovaries. Where other causes have been excluded, we categorized 290 hyperandrogenic women who were seen consecutively for this complaint between 1993 and 2004 into these three subgroups. The aim was to compare the prevalence of obesity, insulin resistance, and dyslipidemia as well as increases in C-reactive protein and homocysteine in these different phenotypes with age-matched ovulatory controls of normal weight (n = 85) and others matched for body mass index (BMI) with women with C-PCOS (n = 42). Although BMI affected fasting serum insulin and the Quantitative Insulin-Sensitivity Check Index, these markers of insulin resistance were greatest in C-PCOS (n = 204), followed by OV-PCOS (n = 50) and then IHA (n = 33). Androgen levels were similar in OV-PCOS and IHA but were higher in C-PCOS, whereas gonadotropins were similar in all groups. Lipid abnormalities were highest in C-PCOS and OV-PCOS and were normal in IHA. C-reactive protein was elevated in C-PCOS and OV-PCOS but not IHA. Homocysteine was elevated only in C-PCOS. Overall, the prevalence of obesity (BMI > 30) was 29% in C-PCOS, 8% in OV-PCOS, and 15% in IHA and insulin resistance (Quantitative Insulin-Sensitivity Check Index < 0.33) was 68% in C-PCOS, 36% in OV-PCOS, and 26% in IHA. The prevalence of having at least one elevated cardiovascular risk marker was 45% in C-PCOS 38% in OV-PCOS and was not increased on IHA (6%). These results suggest that among hyperandrogenic women the prevalence of abnormal metabolic and cardiovascular risk parameters is greatest in C-PCOS, followed by OV-PCOS and then women with IHA. Moreover, in that in OV-PCOS and IHA, ages and weights were similar yet the prevalence of metabolic and cardiovascular risk was greater in OV-PCOS, the finding of polycystic ovaries may be a significant modifying factor.

HOX genes regulate cell differentiation during embryonic development. Here we demonstrate HOXA10 expression in both benign and malignant adult human breast tissue and in MCF-7, but not BT20 breast cancer cells. We have previously shown that HOXA10 mediates uterine differentiation in response to estrogens. The mechanism of action of estradiol and other estrogen receptor modulators on breast cancer cell growth is still poorly understood. MCF-7 cells, which are ER (+) and express HOXA10, were used to assay the effect of estradiol and tamoxifen on HOXA10 expression. Semi-quantitative RT-PCR and northern analysis revealed that treatment with either estradiol or tamoxifen increased HOXA10 mRNA expression. BT20 cells, which are ER (-) and do not endogenously express HOXA10, were used to assay the effect of increased HOXA10 expression on p53 expression and on the invasive phenotype. Constitutively expressing HOXA10 in BT20 cells increased p53 protein expression. Increased HOXA10 also reduced invasiveness through matrigel. The mechanism by which estrogen and other estrogen receptor modulators influence both normal breast development as well as breast cancer may involve the regulation of developmental control genes such as HOXA10; HOXA10 in turn regulates expression of key downstream genes such as p53 and regulates tumor cell functional phenotype.

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