The retinoblastoma protein {pll0 nB) interacts with many cellular proteins in complexes potentially important for its growth-suppressing [unction. We have developed and used an improved version of the yeast two-hybrid system to isolate human cDNAs encoding proteins able to bind pll0 RB. One clone encodes a novel type 1 protein phosphatase catalytic subunit (PP-la2), which differs from the originally defined PP-lc~ by an amino-terminal l 1-amino-acid insert. In vitro-binding assays demonstrated that PP-lc~ isoforms preferentially bind the hypophosphorylated form of p ll0 RB. Moreover, similar pll0 RB sequences are required for binding PP-lc~2 and SV40 large T antigen. Cell cycle synchrony experiments revealed that this association occurs from mitosis to early Gv The implications of these findings on the regulation of both proteins are discussed.
SUMMARY Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/− hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.
The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Apl2, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Apl2 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression ofApl2 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Apl2 encodes a protein with properties known to be characteristic of transcription factor E2F.The retinoblastoma gene (RB), the first tumor suppressor gene identified, encodes a nuclear phosphoprotein which is ubiquitously expressed in vertebrates (19,20,42,44 (45,47), fluctuates with the cell cycle (7, 11, 13); (ii) the unphosphorylated form of RB is present predominantly in the Go-G1 stage (11, 13); (iii) microinjection of unphosphorylated RB into cells at early G1 inhibits their progression into the S phase (22). These data suggest that RB serves as a critical regulator of entry into the cell cycle and that its inactivation in normal cells leads to deregulated growth.How RB functions is the subject of intense inquiry. Two known biochemical properties of the RB protein have been described; one is its intrinsic DNA-binding activity, which was mapped to its C-terminal 300 amino acid residues (44, 66); another is its ability to interact with several oncoproteins of DNA tumor viruses (12,16,67). This interaction was mapped to two discontinuous regions at amino acids 394 to 571 and 649 to 773, designated as the T-binding domains (29,33). Interestingly, mutations of RB protein in tumors were *
A novel class of visible-light-activated TiO 2 photocatalysts were prepared by direct hydrolysis of tetrabutyl titanate through iodine-doping. When calcination temperature is at 673 K, these nanoparticles (mean diameter of ∼5 nm) show stronger absorption in the 400-550 nm range with a red shift in the band gap transition and significantly higher photocatalytic activity than pure TiO 2 prepared by the same procedure and Degussa P-25 titania nanoparticles in aqueous phenol solution under visible light irradiation (λ > 400 nm). Furthermore, I-doped TiO 2 (673 K) still showed pronounced photocatalytic activity under UV and visible light irradiation.
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