The RB1 gene is the first tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer, the pediatric cancer retinoblastoma. The twenty five years of research since its discovery has not only illuminated a general role for RB1 in human cancer, but also its critical importance in normal development. Understanding the molecular function of the RB1 encoded protein, pRb, is a long-standing goal that promises to inform our understanding of cancer, its relationship to normal development, and possible therapeutic strategies to combat this disease. Achieving this goal has been difficult, complicated by the complexity of pRb and related proteins. The goal of this review is to explore the hypothesis that, at its core, the molecular function of pRb is to dynamically regulate the location specific assembly or disassembly of protein complexes on the DNA in response to the output of various signaling pathways. These protein complexes participate in a variety of molecular processes relevant to DNA including gene transcription, DNA replication, DNA repair, and mitosis. Through regulation of these processes, RB1 plays a uniquely prominent role in normal development and cancer.

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Accumulating evidence suggests that regulation of RNA processing through an RNP-driven mechanism is important for coordinated gene expression. This hypothesis predicts that defects in RNP biogenesis will adversely affect the elaboration of specific gene expression programs. To explore the role of RNP biogenesis on mammalian development, we have characterized the phenotype of mice hypomorphic for Thoc1. Thoc1 encodes an essential component of the evolutionarily conserved TREX complex. TREX accompanies the elongating RNA polymerase II and facilitates RNP assembly and recruitment of RNA processing factors. Hypomorphic Thoc1 mice are viable despite significantly reduced Thoc1 expression in the tissues examined. While most tissues of Thoc1-deficient mice appear to develop and function normally, gametogenesis is severely compromised. Male infertility is associated with a loss in spermatocyte viability and abnormal endocrine signaling. We suggest that loss of spermatocyte viability is a consequence of defects in the expression of genes required for normal differentiation of cell types within the testes. A number of the genes affected appear to be direct targets for regulation by Thoc1. These findings support the notion that Thoc1-mediated RNP assembly contributes to the coordinated expression of genes necessary for normal differentiation and development in vivo.The coordinated expression of functionally related genes is required for normal cellular differentiation, development, homeostasis, and responses to environmental stimuli. The combinatorial action of sequence-specific DNA binding transcription factors at promoters provides the foundation for coordinated gene expression. However, even tissue-restricted gene expression is fraught with considerable stochastic noise (2, 28, 39). Furthermore, transcription may be coordinately initiated at genes that vary considerably in length, exon-intron structure, and primary nucleotide sequence. Thus, the speeds and efficiencies of transcriptional elongation, RNA processing, nuclear export, and protein translation may differ considerably from gene to gene. Accumulating evidence indicates that these postinitiation events may be regulated through a ribonucleoprotein particle (RNP)-driven mechanism (25). It has been suggested that dynamic RNP formation may segregate premRNAs into "RNA regulons" to ensure coordinated protein production from functionally related genes (13). Disruption of this regulation is predicted to compromise the elaboration of specific gene expression programs, some of which may affect cellular differentiation and development. In vivo evidence in support of this prediction is lacking, particularly in higher eukaryotes.The evolutionarily conserved TREX protein complex contributes to RNP biogenesis and RNA processing. The metazoan Thoc1 gene and its Saccharomyces cerevisiae functional orthologue HPR1 (both orthologues are subsequently referred to as Thoc1 for simplicity) encode proteins that are essential components of the TREX complex (35). Thoc1 protein (pThoc1) ...

Mutational inactivation of the RB1 tumor suppressor gene initiates retinoblastoma and other human cancers. RB1 protein (pRb) restrains cell proliferation by binding E2f transcription factors and repressing the expression of cell cycle target genes. It is presumed that loss of pRb/E2f interaction accounts for tumor initiation, but this has not been directly tested. RB1 mutation is a late event in other human cancers, suggesting a role in tumor progression as well as initiation. It is currently unknown whether RB1 mutation drives tumor progression and, if so, whether loss of pRb/E2f interaction is responsible. We have characterized tumorigenesis in mice expressing a mutant pRb that is specifically deficient in binding E2f. In endocrine tissue, the mutant pRb has no detectable effect on tumorigenesis. In contrast, it significantly delays progression to invasive and lethal prostate cancer. Tumor delay is associated with induction of a senescence response. We conclude that the pRb/E2f interaction is critical for preventing tumor initiation, but that pRb can use additional context-dependent mechanisms to restrain tumor progression.retinoblastoma gene | cellular senescence | mouse model

Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment.