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Gene Review

lin-35  -  Protein LIN-35

Caenorhabditis elegans

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Disease relevance of lin-35

  • The single C. elegans member of the retinoblastoma gene family, lin-35 Rb, was originally identified as a synthetic Multivulva (synMuv) gene [1] [1].
  • Strong loss-of-function mutations in either efl-1 or dpl-1 cause defects in oogenesis that result in sterility, while lin-35 mutants are fertile with reduced broods [2].

High impact information on lin-35

  • From this screen we have identified fzr-1, a gene that synthetically interacts with lin-35 to produce global defects in cell proliferation control. fzr-1 encodes the C. elegans homolog of Cdh1/Hct1/FZR, a gene product shown in other systems to regulate the APC cyclosome [3].
  • Loss-of-function mutants in other members of the class-B synMuv family, including lin-35, which encodes a protein similar to the tumor suppressor Rb, exhibit a hypersilencing in somatic transgenes similar to that of tam-1 mutants [4].
  • dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development [5].
  • Loss-of-function mutations in two of these genes, dpl-1 DP and efl-1 E2F, caused the same vulval abnormalities as do lin-35 Rb loss-of-function mutations [5].
  • Genetic studies in Caenorhabditis elegans identified lin-9 to function together with the retinoblastoma homologue lin-35 in vulva differentiation [6].

Biological context of lin-35


Anatomical context of lin-35

  • Microarray-based expression profiling of dissected gonads from efl-1, dpl-1 and lin-35 mutants reveals that EFL-1 and DPL-1 promote expression of an extensively overlapping set of target genes, consistent with the expectation that these two proteins function as a heterodimer [2].
  • lin-35 Rb acts in the major hypodermis to oppose ras-mediated vulval induction in C. elegans [10].
  • Our results indicate that lin-35 activity is required in the major hypodermal syncytium and not in the VPCs to inhibit vulval fates [10].

Regulatory relationships of lin-35

  • Loss-of-function alleles of lin-35/Rb and other SynMuv B genes suppress mat-3(ku233) defects by restoring mat-3 mRNA to wild-type levels [11].
  • New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans [12].

Other interactions of lin-35

  • Based on genetic and phenotypic analyses, this role for lin-35 in pharyngeal morphogenesis appears to be distinct from its cell cycle-related functions. lin-35 and ubc-18 may act in concert to regulate the levels of one or more critical targets during C. elegans development [7].
  • These data are consistent with lin-35 Rb, efl-1, and lin-36 acting in a common pathway or complex that negatively regulates G(1) progression [1].
  • In contrast, lin-15B appeared to act in parallel to lin-35 [1].
  • Recently, we demonstrated that lin-35 Rb also acts as a negative regulator of G(1) progression and likely is the major target of cyd-1 Cyclin D and cdk-4 CDK4/6 [1].
  • The level of cyclin E (cye-1) expression is critical for nuclear divisions in the intestine and is elevated in double mutants in lin-35 and RNA interference pathway genes [8].


  1. C. elegans class B synthetic multivulva genes act in G(1) regulation. Boxem, M., van den Heuvel, S. Curr. Biol. (2002) [Pubmed]
  2. Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB). Chi, W., Reinke, V. Development (2006) [Pubmed]
  3. fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen. Fay, D.S., Keenan, S., Han, M. Genes Dev. (2002) [Pubmed]
  4. The RING finger/B-box factor TAM-1 and a retinoblastoma-like protein LIN-35 modulate context-dependent gene silencing in Caenorhabditis elegans. Hsieh, J., Liu, J., Kostas, S.A., Chang, C., Sternberg, P.W., Fire, A. Genes Dev. (1999) [Pubmed]
  5. dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development. Ceol, C.J., Horvitz, H.R. Mol. Cell (2001) [Pubmed]
  6. Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein. Gagrica, S., Hauser, S., Kolfschoten, I., Osterloh, L., Agami, R., Gaubatz, S. EMBO J. (2004) [Pubmed]
  7. lin-35/Rb and ubc-18, an E2 ubiquitin-conjugating enzyme, function redundantly to control pharyngeal morphogenesis in C. elegans. Fay, D.S., Large, E., Han, M., Darland, M. Development (2003) [Pubmed]
  8. Negative regulation of nuclear divisions in Caenorhabditis elegans by retinoblastoma and RNA interference-related genes. Grishok, A., Sharp, P.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. lin-35 Rb and cki-1 Cip/Kip cooperate in developmental regulation of G1 progression in C. elegans. Boxem, M., van den Heuvel, S. Development (2001) [Pubmed]
  10. lin-35 Rb acts in the major hypodermis to oppose ras-mediated vulval induction in C. elegans. Myers, T.R., Greenwald, I. Dev. Cell (2005) [Pubmed]
  11. Caenorhabditis elegans lin-35/Rb, efl-1/E2F and other synthetic multivulva genes negatively regulate the anaphase-promoting complex gene mat-3/APC8. Garbe, D., Doto, J.B., Sundaram, M.V. Genetics (2004) [Pubmed]
  12. New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans. Thomas, J.H., Ceol, C.J., Schwartz, H.T., Horvitz, H.R. Genetics (2003) [Pubmed]
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