RESUMO
Increased rates of ribosome biogenesis and biomass accumulation are fundamental properties of rapidly growing and dividing malignant cells. The MYC oncoprotein drives growth predominantly via its ability to upregulate the ribosome biogenesis program, in particular stimulating the activity of the RNA Polymerase I (Pol I) machinery to increase ribosomal RNA (rRNA) transcription. Although MYC function is known to be highly dependent on the cellular signalling context, the pathways interacting with MYC to regulate transcription of ribosomal genes (rDNA) in vivo in response to growth factor status, nutrient availability and cellular stress are only beginning to be understood. To determine factors critical to MYC-dependent stimulation of rDNA transcription in vivo, we performed a transient expression screen for known oncogenic signalling pathways in Drosophila. Strikingly, from the broad range of pathways tested, we found that ribosomal protein S6 Kinase (S6K) activity, downstream of the TOR pathway, was the only factor rate-limiting for the rapid induction of rDNA transcription due to transiently increased MYC. Further, we demonstrated that one of the mechanism(s) by which MYC and S6K cooperate is through coordinate activation of the essential Pol I transcription initiation factor TIF-1A (RRN 3). As Pol I targeted therapy is now in phase 1 clinical trials in patients with haematological malignancies, including those driven by MYC, these data suggest that therapies dually targeting Pol I transcription and S6K activity may be effective in treating MYC-driven tumours.
Assuntos
DNA Ribossômico/genética , Drosophila melanogaster/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , Proteínas Quinases S6 Ribossômicas/fisiologia , Transcrição Gênica , Animais , Nucléolo Celular/enzimologia , Nucléolo Celular/ultraestrutura , Olho Composto de Artrópodes/enzimologia , Olho Composto de Artrópodes/ultraestrutura , DNA Ribossômico/metabolismo , Drosophila melanogaster/metabolismo , Proteínas Nucleares/metabolismo , Glândulas Salivares/enzimologia , Glândulas Salivares/ultraestrutura , Fatores de Transcrição/metabolismoRESUMO
Nucleotide excision DNA repair (NER) pathway mutations cause neurodegenerative and progeroid disorders (xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD)), which are inexplicably associated with (XP) or without (CS/TTD) cancer. Moreover, cancer progression occurs in certain patients, but not others, with similar C-terminal mutations in the XPB helicase subunit of transcription and NER factor TFIIH. Mechanisms driving overproliferation and, therefore, cancer associated with XPB mutations are currently unknown. Here using Drosophila models, we provide evidence that C-terminally truncated Hay/XPB alleles enhance overgrowth dependent on reduced abundance of RNA recognition motif protein Hfp/FIR, which transcriptionally represses the MYC oncogene homologue, dMYC. The data demonstrate that dMYC repression and dMYC-dependent overgrowth in the Hfp hypomorph is further impaired in the C-terminal Hay/XPB mutant background. Thus, we predict defective transcriptional repression of MYC by the Hfp orthologue, FIR, might provide one mechanism for cancer progression in XP/CS.
Assuntos
Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Transcrição/genética , Animais , Imunoprecipitação da Cromatina , DNA Helicases/genética , Drosophila melanogaster , Regulação da Expressão Gênica , Imuno-Histoquímica , Mutação , Transcrição Gênica , Xeroderma Pigmentoso/genéticaRESUMO
Animal growth requires coordination of cell growth and cell cycle progression with developmental signaling. Loss of cell cycle control is extremely detrimental, with reduced cycles leading to impaired organ growth and excessive proliferation, potentially resulting in tissue overgrowth and driving tumour initiation. Due to the high level of conservation between the cell cycle machinery of Drosophila and humans, the appeal of the fly model continues to be the means with which we can use sophisticated genetics to provide novel insights into mammalian growth and cell cycle control. Over the last decade, there have been major additions to the genetic toolbox to study development in Drosophila. Here we discuss some of the approaches available to investigate the potent growth and cell cycle properties of the Drosophila counterparts of prominent cancer genes, with a focus on the c-Myc oncoprotein and the tumour suppressor protein FIR (Hfp in flies), which behaves as a transcriptional repressor of c-Myc.