A two-hybrid protein interaction screen was used to isolate cDNAs encoding human proteins that can interact with human CDK2 in yeast. A new member of the retinoblastoma susceptibility gene family, Rbr-2 (Rb-related), was obtained. The sequence of the Rbr-2 protein shares -50% identity with p107 and homology to Rb within the pocket domain. Several lines of evidence indicate that Rbr-2 is the adenovirus E1A-associated p130. Like Rb and p107, p130 Rbr-2 can bind to viral oncoproteins, SV40 large T antigen, and adenovirus E1A through its pocket domain. Although p130 Rbr'2 does not bind to CDK2 in vitro, it can interact with cyclins, with a clear preference for D-type cyclins. Because both CDK2 and p130 Rbr'2 show affinity for cyclins, we suggest that p130 Rbr'2 and CDK2 interacted through a yeast-derived cyclin bridge in the two-hybrid screen. The gene encoding p130 Rbr'2 mapped to 16q13, a region of frequent genomic alteration in human tumors.

Cell cycle arrest at the G1 checkpoint allows completion of critical macromolecular events prior to S phase. G1 and G2 checkpoints (4, 5). Phosphorylation of the RB protein by Cdk and the release of RB-associated proteins-e.g., the transcription factor E2F-is correlated with the transition across the G, checkpoint (6-10). The free E2F is then available to transcriptionally activate genes encoding proteins critical for S-phase function, including deoxynucleotide biosynthesis (11).

We have previously shown that human reovirus replication is restricted to cells with an activated Ras pathway, and that reovirus could be used as an effective oncolytic agent against human glioblastoma xenografts. This study examines in more detail the feasibility of reovirus as a therapeutic for breast cancer, a subset of cancer in which direct activating mutations in the ras proto-oncogene are rare, and yet where unregulated stimulation of Ras signaling pathways is important in the pathogenesis of the disease. We demonstrate herein the efficient lysis of breast tumor-derived cell lines by the virus, whereas normal breast cells resist infection in vitro. In vivo studies of reovirus breast cancer therapy reveal that viral administration could cause tumor regression in an MDA-MB-435S mammary fat pad model in severe combined immunodeficient mice. Reovirus could also effect regression of tumors remote from the injection site in an MDA-MB-468 bilateral tumor model, raising the possibility of systemic therapy of breast cancer by the oncolytic agent. Finally, the ability of reovirus to act against primary breast tumor samples not propagated as cell lines was evaluated; we found that reovirus could indeed replicate in ex vivo surgical specimens. Overall, reovirus shows promise as a potential breast cancer therapeutic.

Background: Some patients with low-grade glioma have extraordinarily long survival times; current, early treatment does not prolong their lives. For this reason, therapies that sometimes have neurologic side effects are often deferred intentionally. Methods: In a study of oligodendrogliomas, we used a quantitative method of MR analysis based on the S-transform to investigate whether codeletion of chromosomes1p and19q, a marker of good prognosis, could be predicted accurately by measuring image texture. Results: Differences in texture were seen between tumors with codeletion of chromosomes 1p and 19q and those with intact 1p and 19q alleles on contrast-enhanced T1-weighted and T2-weighted MR images. Quantitative MR texture onT2 images predicted codeletion of chromosomes 1p and 19q with high sensitivity and specificity. Conclusions: This new method of MR image interpretation may have the potential to augment the diagnostic assessment of patients with suspected low-grade glioma.