Adenovirus E1A requires c-Ras for full neoplastic transformation or suppression of differentiation of murine preadipocytes.
We recently demonstrated that the Adenovirus-5 E1A gene products (E1A), known E2F activators, can block the differentiation of murine preadipocytes and that differentiation suppression occurs at lower levels than required for full neoplastic transformation. Progressively higher levels were accompanied by apoptosis induction. To examine the role of the cellular Ras protooncogene product (Ras) in E1A function, E1A was expressed in C3H10T(1/2) (10T(1/2))-derived preadipocytes rendered deficient in Ras activity by transfection with inducible or constitutive antisense ras gene constructs (Ras-knockdowns). The results showed that, although even low amounts of E1A could block the differentiation of 10T(1/2) preadipocytes with normal Ras levels, even the highest E1A levels were unable to block the differentiation or induce transformation of Ras-knockdown preadipocytes. Ras downregulation did not affect E2F activation by E1A. Interestingly, our results further demonstrated a dramatic reduction in the levels of the E1A protein itself as differentiation progressed, with a concomitant reduction in E1A's ability to induce apoptosis as a result. These findings suggest for the first time that Ras, although cytoplasmic, is an integral component of the pathway whereby E1A, an oncoprotein believed to have primarily nuclear targets, suppresses differentiation or induces neoplastic conversion of murine preadipocytes.
Cao
J
J
Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada.
Arulanandam
R
R
Vultur
A
A
Anagnostopoulou
A
A
Raptis
L
L
D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D015967:Gene Expression Regulation, Viral; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D014162:Transfection
D017500:Adenovirus E1A Proteins; D016283:Proto-Oncogene Proteins p21(ras)