p14ARF inhibits the growth of p53 deficient cells in a cell-specific manner

Abstract

While p14(ARF) suppression of tumorigenesis in a p53-dependent manner is well studied, the mechanism by which p14(ARF) inhibits tumorigenesis independently of p53 remains elusive. A variety of factors have been reported to play a role in this latter process. We report here that p14(ARF) displays different effects on the anchorage-dependent and -independent growth of p53-null/Mdm2 wild type cells. p14(ARF) blocks both the anchorage-dependent and-independent (soft agar) proliferation of 293T and p53(-/-) HCT116, but not p53-null H1299 lung carcinoma cells. While p14(ARF) had no effect on the anchorage-dependent proliferation of p53(-/-) MEFs and Ras12V-transformed p53(-/-) MEFs, it inhibited the growth of Ras12V-transformed p53(-/-) MEFs in soft agar. Furthermore, ectopic expression of p14(ARF) did not lead to degradation of the E2F1 protein and did not result in the reduction of E2F1 activity detected by two E2F1 responsible promoters, Apaf1 and p14(ARF) promoter, in 293T, p53(-/-) HCT116, and H1299 cells. This is consistent with our observations that p14(ARF) did not result in G1 arrest, but induced apoptosis via Bax up-regulation. Taken together, our data demonstrate that the response of p53-null cells to ARF is cell type dependent and involves factors other than Mdm2 and E2F1.

p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner

“…Adenovirus-mediated p14ARF overexpression induces cell cycle arrest and/or apoptosis in multiple cell lines with intact or disrupted p53. 36,37 However, several reports show that stable transfection-mediated p14ARF expression can not induce cell cycle arrest or apoptosis in certain cell lines regardless of p53 status, 19,38,39 which is similar to our results that stable p14ARF transfection did not arrest cell cycle or induce apoptosis in U2OS and MG63 cells. These findings raised several possibilities.…”

“…18 Moreover, ectopic expression of p14ARF induces growth inhibition or apoptosis in p53-null cells. [19][20][21] However, most of the p53-independent activities of p14ARF remain controversial and largely elusive.…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…9A, lanes 2-5). However, ARF did not decrease MAGE-A11 levels further in the presence of E2F1, and ARF did not promote the degradation of E2F1, in agreement and in contrast to previous reports (41,51).…”

p14ARF Regulates E2F-1 Ubiquitination and Degradation via a p53-Dependent Mechanism

“…[30][31][32] In a series of reports, ARF was shown to interact with E2F-1, and this interaction prevented the formation of active E2F-1 transcriptional complexes, 46 inhibited E2F-1 transactivation potential 30,31 and promoted the proteasome dependent degradation of E2F-1. 32 A recent study suggested that p53 may be required for the degradation of E2F-1 by ARF 47 and we now conclusively demonstrate that ARF-induced ubiquitination and degradation of the E2F-1 transcription factor occurs via a p53-dependent pathway.…”