{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T07:50:55Z","timestamp":1760255455310},"reference-count":34,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,8,1]],"date-time":"2011-08-01T00:00:00Z","timestamp":1312156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2012,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The small GTPase proteins, Ras and Rheb, serve as molecular switches regulating cell proliferation, differentiation and apoptosis. Ras also regulates Rheb by inactivating the tuberous sclerosis complex (TSC), which includes products of the <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> genes encoding hamartin (TSC1) and tuberin (TSC2), respectively, and acts as a Rheb\u2010specific GTPase\u2010activating protein. Loss of function of TSC1 or TSC2 results in an increase in active Rheb.GTP with the consequent translational abnormalities and excessive cell proliferation characteristic of the genetic disorders, tuberous sclerosis and lymphangioleiomyomatosis (LAM). To determine whether inactivation of Rheb, Ras or both might be a potential treatment for LAM, we used TSC2\u2010null ELT3 cells as a LAM model. The cells were treated with the Ras inhibitor <jats:italic>S<\/jats:italic>\u2010<jats:italic>trans<\/jats:italic>,<jats:italic>trans<\/jats:italic>\u2010farnesylthiosalicylic acid (FTS; salirasib), which mimics the C\u2010terminal <jats:italic>S<\/jats:italic>\u2010farnesyl cysteine common to Ras and Rheb. This C\u2010terminus is critical for their attachment to cellular membranes and for their biological activities. Untreated, the ELT3 cells expressed significant amounts of Rheb but little Ras.GTP, and this phenotype was reversed by TSC2 reexpression. Treatment with FTS decreased Ras.GTP only slightly in the TSC2\u2010null cells, but reduced their overactive Rheb as well as their proliferation, migration and tumor growth. Notably, TSC2 reexpression in these ELT3 cells rescued them from the inhibitory effect of FTS. Evidently, therefore, FTS blocks active Rheb in TSC2\u2010null ELT3 cells and may have therapeutic potential for LAM.<\/jats:p>","DOI":"10.1002\/ijc.26139","type":"journal-article","created":{"date-parts":[[2011,4,16]],"date-time":"2011-04-16T03:28:56Z","timestamp":1302924536000},"page":"1420-1429","source":"Crossref","is-referenced-by-count":14,"title":["Farnesylthiosalicylic acid (salirasib) inhibits Rheb in TSC2\u2010null ELT3 cells: A potential treatment for lymphangioleiomyomatosis"],"prefix":"10.1002","volume":"130","author":[{"given":"Victoria","family":"Makovski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roni","family":"Haklai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoel","family":"Kloog","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,8]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200705-061VS"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21419"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/107327480601300405"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00113303"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300226200"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2004.03.019"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.03.220"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1105"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389450053765833"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04869"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi972032d"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm801165r"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202678200"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205698200"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201005"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25367"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2005.05.015"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1878"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.10281"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M402591200"},{"key":"e_1_2_6_22_2","first-page":"1568","article-title":"Rodent model of reproductive tract leiomyomata. 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