ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways

Zhang, Yanping; Xiong, Yue; Yarbrough, Wendell G.

doi:10.1016/s0092-8674(00)81401-4

Cited by 1,497 publications

(1,206 citation statements)

References 38 publications

Supporting

Mentioning

1,158

Contrasting

Unclassified

Order By: Relevance

“…Moreover, as both gene products are often mutated in the same tumor, one might question if p19-ARF loss could also be related to the RB overexpression seen in p16 negative tumors. It would appear that such a relationship does not exist, since p19-ARF inhibits cell cycle progression through a p53 rather than an RB pathway by promoting MDM2 degradation and stabilizing wild-type p53 (Pomerantz et al, 1998, Zhang et al, 1998. Nevertheless, the simultaneous loss of both p16 and p19-ARF could be a major factor in the overall prognosis of certain individuals with bladder cancer who do not have additional mutations in p53 which should become evident from the discussions below.…”

Section: Discussionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

View full text Add to dashboard Cite

Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

View full text Add to dashboard Cite

show abstract

“…It is generally accepted that hyperphosphorylation of Rb allows its release of the bound E2F factors (Nevins, 1992;Weinberg, 1995), leading to activation of E2F-responsive genes (Trimarchi and Lees, 2002). One of the targets is the gene encoding the p19ARF, which is a key component of the p19ARF-MDM2-p53 network (Zhang et al, 1998;Zhu et al, 1999;Trimarchi and Lees, 2002). Activation of p19ARF inhibits MDM2, a p53 ubiquitin ligase, enhancing p53 stabilization (Momand et al, 1992;Kubbutat et al, 1997;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998;Haupt et al, 1999;Honda and Yasuda, 1999;Weber et al, 1999;Llanos et al, 2001;Zindy et al, 2003).…”

Section: Dephosphorylation Of P53 Displays Strong Impact On Its Functmentioning

confidence: 99%

“…One of the targets is the gene encoding the p19ARF, which is a key component of the p19ARF-MDM2-p53 network (Zhang et al, 1998;Zhu et al, 1999;Trimarchi and Lees, 2002). Activation of p19ARF inhibits MDM2, a p53 ubiquitin ligase, enhancing p53 stabilization (Momand et al, 1992;Kubbutat et al, 1997;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998;Haupt et al, 1999;Honda and Yasuda, 1999;Weber et al, 1999;Llanos et al, 2001;Zindy et al, 2003). This explains why inhibition of PP-1 activity could lead to observed p53 upregulation in rabbit and rat lens epithelial cells (Li et al, 1998(Li et al, , 2001a.…”

Section: Dephosphorylation Of P53 Displays Strong Impact On Its Functmentioning

confidence: 99%

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

et al. 2006

View full text Add to dashboard Cite

We have previously demonstrated that the serine/threonine protein phosphatase-1 (PP-1) plays an important role in promoting cell survival. However, the molecular mechanisms by which PP-1 promotes survival remain largely unknown. In the present study, we provide evidence to show that PP-1 can directly dephosphorylate a master regulator of apoptosis, p53, to negatively modulate its transcriptional and apoptotic activities, and thus to promote cell survival. As a transcriptional factor, the function of p53 can be greatly regulated by phosphorylation and dephosphorylation. While the kinases responsible for phosphorylation of the 17 serine/threonine sites have been identified, the dephosphorylation of these sites remains largely unknown. In the present study, we demonstrate that PP-1 can dephosphorylate p53 at Ser-15 and Ser-37 through co-immunoprecipitation, in vitro and in vivo dephosphorylation assays, overexpression and silence of the gene encoding the catalytic subunit for PP-1. We further show that mutations mimicking constitutive dephosphorylation or phosphorylation of p53 at these sites attenuate or enhance its transcriptional activity, respectively. As a result of the changed p53 activity, expression of the downstream apoptosis-related genes such as bcl-2 and bax is accordingly altered and the apoptotic events are either largely abrogated or enhanced. Thus, our results demonstrate that PP-1 directly dephosphorylates p53, and dephosphorylation of p53 has as important impact on its functions as phosphorylation does. In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

show abstract

“…Studies on Adenovirus E1A demonstrate that p53 stabilization is mediated by the activation of E2F-1, which in turn stimulates the transcription of the tumour suppressor p19 ARF gene . p19 ARF associates with and inhibits Mdm2 (Kamijo et al, 1998;Pomerantz et al, 1998;Stott et al, 1998;Zhang et al, 1998), which acts in a feedback loop to antagonize p53 function by direct binding (Barak et al, 1993;Wu et al, 1993). Mdm2 association with p53 inhibits p53 transcriptional activity (Momand et al, 1992;Oliner et al, 1993), induces p53 ubiquitination (Haupt et al, 1997;Honda et al, 1997;Kubbutat et al, 1997) and accelerates p53 nuclear export and its degradation in cytoplasmic proteosomes (Roth et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

et al. 2000

View full text Add to dashboard Cite

The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not su cient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent ®broblasts. Our ®ndings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19 ARF , does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.

show abstract

ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways

Cited by 1,497 publications

References 38 publications

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

Contact Info

Product

Resources

About