Article thumbnail

Coordinated Regulation of Intestinal Functions in C. elegans by LIN-35/Rb and SLR-2

By Natalia V. Kirienko, John D. K. McEnerney and David S. Fay

Abstract

LIN-35 is the sole C. elegans representative of the pocket protein family, which includes the mammalian Retinoblastoma protein pRb and its paralogs p107 and p130. In addition to having a well-established and central role in cell cycle regulation, pocket proteins have been increasingly implicated in the control of critical and diverse developmental and cellular processes. To gain a greater understanding of the roles of pocket proteins during development, we have characterized a synthetic genetic interaction between lin-35 and slr-2, which we show encodes a C2H2-type Zn-finger protein. Whereas animals harboring single mutations in lin-35 or slr-2 are viable and fertile, lin-35; slr-2 double mutants arrest uniformly in early larval development without obvious morphological defects. Using a combination of approaches including transcriptome profiling, mosaic analysis, starvation assays, and expression analysis, we demonstrate that both LIN-35 and SLR-2 act in the intestine to regulate the expression of many genes required for normal nutrient utilization. These findings represent a novel role for pRb family members in the maintenance of organ function. Our studies also shed light on the mechanistic basis of genetic redundancy among transcriptional regulators and suggest that synthetic interactions may result from the synergistic misregulation of one or more common targets

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2312330
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2001). A gene expression map for Caenorhabditis elegans.
  2. (1986). A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.
  3. (2004). A new class of C. elegans synMuv genes implicates a Tip60/NuA4-like HAT complex as a negative regulator of Ras signaling.
  4. (1998). A new marker for mosaic analysis in Caenorhabditis elegans indicates a fusion between hyp6 and hyp7, two major components of the hypodermis.
  5. (1989). A point mutational analysis of human papillomavirus type 16 E7 protein.
  6. (1987). A trans-spliced leader sequence on actin mRNA in C. elegans.
  7. (2000). Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions.
  8. (2002). Axenic growth up-regulates mass-specific metabolic rate, stress resistance, and extends life span in Caenorhabditis elegans.
  9. Brehm A (2005) E2F-Rb complexes regulating transcription of genes important for differentiation and development.
  10. (2002). C. elegans class B synthetic multivulva genes act in G(1) regulation.
  11. (2006). C. elegans DAF-18/PTEN mediates nutrient-dependent arrest of cell cycle and growth in the germline.
  12. (2007). C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions.
  13. (1996). Conservation of function and expression of unc119 from two Caenorhabditis species despite divergence of non-coding DNA.
  14. (1997). Control of the G1/S transition.
  15. (2001). daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans.
  16. (2000). EAT-20, a novel transmembrane protein with EGF motifs, is required for efficient feeding in Caenorhabditis elegans.
  17. (1991). Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences.
  18. (2007). Function of the Caenorhabditis elegans ABC transporter PGP-2 in the biogenesis of a lysosome-related fat storage organelle.
  19. (2002). fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen.
  20. (2006). Gastrointestinal phenotype of ATR-X syndrome.
  21. (2006). Genetic Mapping and Manipulation. WormBook (The C elegans Research Community,
  22. (2004). Global mapping of the yeast genetic interaction network.
  23. (2006). gon-14 functions with class B and class C synthetic multivulva genes to control larval growth in Caenorhabditis elegans.
  24. (1987). Human retinoblastoma susceptibility gene: cloning, identification, and sequence.
  25. (2006). Inactivation of conditional Rb by Villin-Cre leads to aggressive tumors outside the gastrointestinal tract.
  26. (2007). Large-scale RNAi screens identify novel genes that interact with the C. elegans retinoblastoma pathway as well as splicing-related components with synMuv B activity.
  27. (1998). lin-35 and lin-53, two genes that antagonize a C. elegans Ras pathway, encode proteins similar to Rb and its binding protein RbAp48.
  28. (2005). lin-35 Rb acts in the major hypodermis to oppose ras-mediated vulval induction in C.
  29. (2007). lin-35/Rb and the CoREST ortholog spr-1 coordinately regulate vulval morphogenesis and gonad development in C.
  30. (2003). lin-35/Rb and ubc-18, an E2 ubiquitin-conjugating enzyme, function redundantly to control pharyngeal morphogenesis in C.
  31. (2004). lin-35/Rb and xnp-1/ATR-X function redundantly to control somatic gonad development in C.
  32. (2004). lin-35/Rb cooperates with the SWI/SNF complex to control Caenorhabditis elegans larval development.
  33. (2006). Loss of LIN-35, the Caenorhabditis elegans ortholog of the tumor suppressor p105Rb, results in enhanced RNA interference.
  34. Maintenance of C. elegans WormBook (The C elegans Research Community,
  35. (1986). Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas.
  36. (2000). Mosaic analysis in Caenorhabditis elegans.
  37. (2006). Nomarski images for learning the anatomy, with tips for mosaic analysis.
  38. (2007). pRb-mediated control of epithelial cell proliferation and Indian hedgehog expression in mouse intestinal development.
  39. (2004). Principles of tumor suppression.
  40. (2007). protein to promote programmed cell death in Caenorhabditis elegans.
  41. (2005). Retinoblastoma family 2 is required in vivo for the tissue-specific repression of dE2F2 target genes.
  42. (2006). Retinoblastoma family genes.
  43. (2006). Retinoblastoma family proteins: insights gained through genetic manipulation of mice.
  44. (2001). Retinoblastoma protein partners.
  45. (2006). Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Exp Biol Med (Maywood)
  46. (2005). Reverse Genetics. WormBook (The C elegans Research Community,
  47. (1998). RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis.
  48. (2003). Role of the RB tumor suppressor in cancer.
  49. (2005). Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants.
  50. (2006). SynMuv genes redundantly inhibit lin-3/EGF expression to prevent inappropriate vulval induction in C.
  51. (2000). Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization.
  52. (2005). The cell cycle and development: lessons from
  53. (2004). The coordinate regulation of pharyngeal development in C. elegans by lin-35/Rb, pha-1, and ubc-18.
  54. (2006). The ELT-2 GATA-factor and the global regulation of transcription in the C. elegans intestine.
  55. (1989). The multivulva phenotype of certain Caenorhabditis elegans mutants results from defects in two functionally redundant pathways.
  56. (1995). The ncl-1 gene and genetic mosaics of Caenorhabditis elegans.
  57. (1998). The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin-mediated gene expression.
  58. (2006). The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.
  59. (2002). The RB and p53 pathways in cancer.
  60. (2006). The related retinoblastoma (pRb) and p130 proteins cooperate to regulate homeostasis in the intestinal epithelium.
  61. (1995). The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein.
  62. (1999). The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis.
  63. (2007). The SynMuv genes of Caenorhabditis elegans in vulval development and beyond.
  64. (2007). The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes.
  65. (2007). Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles.