IndraLab

"For example, while Myc binds to E-boxes of the p16 promoter and up-regulates p16 transcription, it has also been demonstrated that Myc can activate Bmi1, a potent repressor of the entire INK4b/ARF/INK4a locus."

"These findings imply that let-7g might function as an inhibitor of HCC cell proliferation through direct repression of c-Myc, which may lead to re-expression of the tumor suppressor p16INK4A [XREF_BIBR]."

"We have shown that the cyclin dependent kinase Cdk2, although redundant for cell cycle progression, has a unique role in suppressing a Myc induced senescence program : Myc activation elicited expression of p16 (INK4a) and p21 (Cip1), and caused senescence in cells lacking Cdk2, but not in Cdk2-proficient cells."

"studies showing that the ARF gene encoded by the tumor-suppressive gene locus, INK4A, is induced after expression of c-MYC or other mitogenic transcription factors, like E2F [33]. The authors suggest that activation of cell cycle deregulating genes is translated into activation of the ARF gene, which encodes a p53-stabilizing protein [34]. Consistent with this model, fibroblasts from ARF-/- mice are largely refractory to c-MYC-induced apoptosis"

"XREF_BIBR, XREF_BIBR, XREF_BIBR Furthermore, c-MYC has been reported to directly induce the expression of p19 and ARF, which also belongs to the INK4 locus."

"For example, physiologic thresholds of Myc and Ras signaling do not activate Arf gene expression, but overexpression of Myc and oncogenic Ras induces Arf."

"In these cell types, Myc induces the expression of p19 Arf, which, by inactivating Mdm2, helps to enhance p53 dependent apoptosis (Zindy et al., 1998)."

"Oncogenic c-Myc can indirectly induce the expression of the tumor suppressor ARF, which leads to apoptosis through the stabilization of p53, but both c-Myc and ARF have apoptotic activities that are independent of p53."

"In addition, both c-Myc and E2F-1 induce Arf expression."

"For example, MYC induces the expression of the tumor suppressor ARF."

"For instance, in the Emu-myc murine model of lymphoma, sustained over-expression of Myc signaling induces p19 Arf expression, resulting in apoptosis through the inhibition of Mdm2 and stabilization of the p53 tumor suppressor protein."

"Myc overexpression induces p53 dependent apoptosis in part by inducing expression of the Mdm2-antagonist Arf and in part by promoting a DNA-damage response (DDR)."

"Subsequent upregulation of the Epstein-Barr virus nuclear antigen 3C (EBNA3C) results in reduced c-Myc expression, attenuated DDR/R activity, and repressed p16 INK4A and p14 ARF expression, favoring t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"A previous study showed that c-Myc overexpression not only induced p14ARF transcription but also stabilized p14ARF by inhibiting the ubiquitin ligase activity of ULF in normal fibroblast cells."

"from full text - Box 2 | Bcl2 and the Rb/Arf/p53 network Inactivation of the retinoblastoma (Rb) pathway — for example, by loss of cell-cycle inhibitor Ink4a, which can prevent cyclin-D–Cdk4 from phosphorylating Rb — unleashes the transcription factor E2f1,which increases expression of Arf, a protein that is encoded by the same locus as Ink4a (REF. 136).Arf,which is also a transcriptional target of Myc, sequesters Mdm2, a negative regulator of p53. Raised p53 levels can either impose growth arrest, typically by inducing the Waf1 cell-cycle inhibitor, or promote apoptosis through targets such as Bax, Puma and Noxa. The apoptotic targets seem to also require the p53 relative p63 or p73 (REF. 152). Circles/ovals denote oncogene products; rectangles denote known or likely tumour suppressors. For more detail, see REFS 4–6,136.ATM, ataxia telengiectasia mutated; Chk2, checkpoint 2; NF-?B, nuclear factor-?B."