Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where they can bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs may act directly on target cells, or they can be released through digestion of the ECM or the activity of a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimately resulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most play important roles in embryonic development and wound healing. FGF signaling also appears to play a role in tumor growth and angiogenesis, and autocrine FGF signaling may be particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state.

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Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.

Human breast tumorigenesis is promoted by the estrogen receptor pathway, and nuclear receptor coactivators are thought to participate in this process. Here we studied whether one of these coactivators, AIB1 (amplified in breast cancer 1), was rate-limiting for hormonedependent growth of human MCF-7 breast cancer cells. We developed MCF-7 breast cancer cell lines in which the expression of AIB1 can be modulated by regulatable ribozymes directed against AIB1 mRNA. We found that depletion of endogenous AIB1 levels reduced steroid hormone signaling via the estrogen receptor ␣ or progesterone receptor ␤ on transiently transfected reporter templates. Down-regulation of AIB1 levels in MCF-7 cells did not affect estrogen-stimulated cell cycle progression but reduced estrogen-mediated inhibition of apoptosis and cell growth. Finally, upon reduction of endogenous AIB1 expression, estrogen-dependent colony formation in soft agar and tumor growth of MCF-7 cells in nude mice was decreased. From these findings we conclude that, despite the presence of different estrogen receptor coactivators in breast cancer cells, AIB1 exerts a rate-limiting role for hormone-dependent human breast tumor growth.Human breast tumorigenesis is promoted by enhanced activity of the estrogen receptor (ER) 1 pathway. It has been shown that estrogens can directly cause proliferation of breast cancer cells (1) and that more than 70% of primary human breast cancers are ER-positive. The activity of the ER is modulated by a recently discovered class of specific corepressors and coactivators that inhibit or enhance the transcriptional activity of the ER as well as related nuclear hormone receptors (2-4). In the absence of ligand, some of the nuclear receptors are bound to corepressors such as SMRT and NCoR (5,6). After ligand binding, the corepressors are released, and nuclear receptor coactivators are recruited. This leads to the enhancement of transcriptional activity of the nuclear receptor via interaction with chromatin remodeling complexes and members of the basal transcription machinery (2, 3).Some of the best characterized nuclear receptor coactivators belong to the p160/steroid receptor coactivator (SRC) family. In humans, this family consists of SRC-1 (7), TIF-2 (8), and AIB1 (9) (ACTR/RAC3/TRAM-1/SRC-3) (10 -13). Special attention has been focused on the gene AIB1 (amplified in breast cancer 1), which is amplified in breast, ovarian, pancreatic, and gastric cancer (9,14,15). Amplification of the AIB1 gene was detected in 5-10% of primary breast tumors, and AIB1 mRNA was found to be highly expressed in many breast tumor specimens (9, 16 -18). Furthermore, AIB1 amplification correlates with estrogen and progesterone receptor positivity of primary breast tumors as well as with tumor size (16,19). AIB1 binds directly to ER in vivo (20) and enhances in vitro the transcriptional activity of the estrogen receptor (9, 10, 13) as well as a number of other nuclear receptors, including the progesterone, thyroid hormone, and retinoid acid receptor (10 -12)....

The interleukin-2 CD28 response element (CD28RE) acts as a composite enhancer, in conjunction with a 3-12-O-tetradecanoylphorbol-13-acetate response element (TRE)-like element, to confer CD28 receptor-dependent inducibility to the interleukin-2 promoter in T-cells. When inserted as a single copy upstream of a basal promoter, this composite enhancer, termed the CD28RE-TRE, is both highly active and CD28-inducible in transactivation assays. A multicomponent nuclear protein complex that binds the CD28RE-TRE was isolated by DNA affinity chromatography from nuclear extracts of mitogen-and CD28 receptor-costimulated human T-cells. Immunological and biochemical analyses of this complex reveal the presence of c-Rel, ATF-1, and CREB2 as major DNA-binding components. Coexpression of c-Rel in combination with ATF-1, CREB2, or ATF-1/CREB2 leads to synergistic transactivation of a CD28RE-TRE reporter plasmid in quiescent Jurkat Tcells. Furthermore, CD28-dependent transactivation of the CD28RE-TRE is specifically inhibited by cAMP response element-binding protein (CREB) dominant-negative expression vectors. Moreover, mutant promoter constructs in which the internal 5-CD28RE and 3-TRElike sequences have been topologically positioned 180°o ut of phase with one another show loss of mitogen-and CD28-dependent inducibility. Finally, the addition of the CREB-binding transcriptional coactivator p300 leads to a dramatic CREB-dependent increase in both mitogen-and CD28-mediated transactivation of the CD28RE-TRE. These findings demonstrate that full physiological responsiveness to CD28 receptor stimulation in T-cells is dependent on topologically linked sequences within the CD28RE-TRE composite enhancer and provide strong support of a direct role for the CREB family of transcription factors and p300/CREB-binding protein coactivator proteins in cytokine gene induction during T-cell activation.The extensive characterization of the molecular processes governing immune activation of T-lymphoctyes has produced one of the most instructive and informative model systems in the field of signal transduction biology (1-3). A major area of interest to both signal transduction biologists and immunologists has been the elucidation of the mechanisms through which combined signals, derived from the T-cell surface, are integrated to achieve specific biological responses in the activated T-cell. In the case of T-lymphocyte immune activation, the generation of a fully functional immune response is dependent on the integration of dual signals that originate from cellcell interactions between the antigen-reactive T-cell and the antigen-presenting B-cell or macrophage. The first of these signals is provided by the T-cell receptor, which makes contact with its target antigen in the context of the major histocompatibility complex type II receptor on the surface of the antigen-presenting cell. In cell culture systems, this first antigen receptor-dependent signal can be replaced pharmacologically by mitogenic combinations such as ionomycin and phorbol 12-myrist...