High impact information on let-60

• Here we show that the let-7 family negatively regulates let-60/RAS [1].
• Our genetic analysis showed ksr-1 positively mediates Ras signaling and functions downstream of or in parallel to let-60 [2].
• Genetic epistasis analysis suggests that ksr-1 acts downstream of or in parallel to let-60 ras [3].
• Extrachromosomal arrays of let-60 ras DNA cause cell-type misspecification (extra vulval fates) phenotypically opposite to that caused by let-60 ras loss-of-function mutations (no vulval fates), and suppress the vulvaless phenotype of mutations in two other genes necessary for vulval induction [4].
• We have cloned the let-60 gene, and shown that it encodes a gene product identical in 84% of its first 164 amino acids to ras gene products from other vertebrate and invertebrate species [4].

Biological context of let-60

• Genetic epistasis experiments indicate that lin-25 is required in the inductive signaling pathway downstream of let-60 Ras and the Raf/MAP kinase cascade [5].
• Vulval development in the nematode Caenorhabiditis elegans can be divided into a fate specification phase controlled in part by let-60 Ras, and a fate execution phase involving stereotypical patterns of cell division and migration controlled in part by lin-17 Frizzled [6].
• The let-60 ras gene of Caenorhabditis elegans is one of the key players in a signal transduction pathway that controls the choice between vulval and epidermal differentiation in response to extracellular signals [7].
• Gain-of-function let-60 ras alleles rescued the defects associated with ptp-2(op194), suggesting that LET-60 Ras acts downstream of, or in parallel to, PTP-2 during oogenesis [8].
• The penetrance of the multivulva phenotype caused by loss-of-function mutations in lin-15, and gain-of-function mutations in let-23 or let-60 ras, was reduced by ptp-2(op194) [8].

Anatomical context of let-60

• The let-60 gene, an essential ras gene of the nematode Caenorhabditis elegans, acts as a switch in the inductive signalling pathway that initiates vulva formation [9].
• A mosaic analysis demonstrated that let-60 ras is required within the sex myoblasts to control proper positioning [10].
• Finally, we have also investigated genetic interactions between let-60 ras and other genes important for sex myoblast migration, including egl-15, which encodes a fibroblast growth factor receptor tyrosine kinase (D. L. DeVore, H. R. Horvitz and M. J. Stern (1995) Cell 83, 611-623) [10].
• In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line [11].

Associations of let-60 with chemical compounds

• Many genes required for vulval induction have been identified, including the let-23 receptor tyrosine kinase gene and the let-60 ras gene [12].
• We show here that two farnesyltransferase inhibitors, manumycin and gliotoxin, suppress the Multivulva phenotype resulting from an activated let-60 ras mutation, but not the Multivulva phenotype resulting from mutations in the lin-1 gene or the lin-15 gene, which act downstream and upstream of let-60 ras, respectively, in the signaling pathway [13].

Regulatory relationships of let-60

• A loss-of-function mutation in gap-1 suppresses the vulvaless phenotype of mutations in the let-60 ras signaling pathway, but a gap-1 single mutant does not exhibit excess vulval induction [14].
• Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activated let-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation [15].
• Mutants lacking lin-1 activity display a phenotype similar to that caused by mutations that constitutively activate let-60 Ras consistent with a model in which lin-1 is a repressor of the 1 degree fate whose activity is inhibited by phosphorylation by MPK-1 MAP kinase [16].
• To identify components acting downstream of let-60 ras in the vulval signaling pathway, we have identified a reduction-of-function mutation in the sur-1 gene that completely suppresses the multivulva phenotype of a hyperactive let-60 ras mutation [7].
• New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans [17].

Other interactions of let-60

• Microinjection of a gain-of-function mek-2 mutation resulted in Muv and other mutant phenotypes, whereas microinjection of a dominant-negative mutation not only suppressed the Muv phenotype of an activated let-60 ras mutation but also caused an egg-laying defective phenotype in otherwise wild type animals [18].
• Genes necessary for this induction include the lin-3 growth factor, the let-23 receptor tyrosine kinase, and let-60 ras. lin-15 is a negative regulator of this inductive pathway [19].
• We discuss the similarities and differences between the cellular defects seen in Rac mutants and let-60 Ras or lin-17 Frizzled mutants [6].
• We identified cgr-1 by screening for suppressors of the ectopic vulval cell fates caused by a gain-of-function mutation of the let-60 ras gene [20].
• C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation [21].

Analytical, diagnostic and therapeutic context of let-60

• The behavior of individual cells was analyzed in a let-60/ras mutant by three-dimensional confocal microscopy [22].
• We have used DNA microarrays to identify 708 genes that change expression in response to activated let-60 Ras [11].

References