The retinoblastoma protein is required for Ras-induced oncogenic transformation.
Most human cancers involve either mutational activation of the Ras oncogenic pathway and/or inactivation of the retinoblastoma tumor suppressor (RB) pathway. Paradoxically, tumors that harbor Ras mutations almost invariably retain expression of a wild-type pRB protein. We explain this phenomenon by demonstrating that Ras-induced oncogenic transformation surprisingly depends on functional pRB protein. Cells lacking pRB are less susceptible to the oncogenic actions of H-RasV12 than wild-type cells and activated Ras has an inhibitory effect on the proliferation of pRB-deficient human tumor cells. In addition, depletion of pRB from Ras-transformed murine cells or human tumor cells that harbor Ras pathway mutations inhibits their proliferation and anchorage-independent growth. In sharp contrast to pRB-/- 3T3 cells, fibroblasts deficient in other pRB family members (p107 and p130) are more susceptible to Ras-mediated transformation than wild-type 3T3 cells. Moreover, loss of pRB in tumor cells harboring a Ras mutation results in increased expression of p107, and overexpression of p107 but not pRB strongly inhibits proliferation of these tumor cells. Together, these findings suggest that pRB and p107 have distinct roles in Ras-mediated transformation and suggest a novel tumor-suppressive role for p107 in the context of activated Ras.
Williams
Jonathan P
JP
MGH Cancer Center and Harvard Medical School, Bldg. 149, 13th St., Charlestown, MA 02129, USA.
Stewart
Timothy
T
Li
Bihua
B
Mulloy
Roseann
R
Dimova
Dessislava
D
Classon
Marie
M
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016161:Genes, Retinoblastoma; D011905:Genes, ras; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency / Q000235:genetics; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000235:genetics
D034741:RNA, Small Interfering; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130