Journal article
The alternative reading frame tumor suppressor inhibits growth through p21-dependent and p21-independent pathways
Cancer research (Chicago, Ill.), Vol.61(7), pp.3145-3150
2001
PMID: 11306500
Abstract
The alternative reading frame (ARF) tumor suppressor mediates growth arrest or apoptosis through activation of the p53 tumor suppressor. A prevailing concept is that ARF uses p21Cip1/Waf1, a p53-responsive gene and cyclin-dependent kinase (Cdk) inhibitor, to block cell cycle progression. Using p21 nullizygous cells, we demonstrate that p21 is nonessential for the antiproliferative activity of ARF and p53, although it likely governs the arrest through Cdk inactivation when present. ARF overexpression in p21-positive and p21-negative mouse embryo fibroblasts (MEFs), but not in primary cells lacking p53, induced a biphasic (G1 and G2) cell cycle arrest. The ARF-induced growth arrest, regardless of p21 status, coincided with activation of p53 and accumulation of hypophosphorylated retinoblastoma protein (retinoblastoma protein). In ARF-arrested p21-positive cells, the presence of growth-inhibitory retinoblastoma protein correlated with an absence of Cdk2-dependent kinase activity, an increase in p21 association with inactive Cdks, and a lack of cyclin A expression. In contrast, p21-/- mouse embryo fibroblasts were arrested by ARF despite containing elevated levels of cyclin A protein and highly active Cdk2-dependent kinases. These findings provide evidence that ARF can block growth through a p21-independent pathway(s) that overrides Cdk2 activation.
Details
- Title: Subtitle
- The alternative reading frame tumor suppressor inhibits growth through p21-dependent and p21-independent pathways
- Creators
- Modestos MODESTOU - Department of Pharmacology and the Molecular Biology Graduate Program, The University of Iowa, College of Medicine, Iowa City, Iowa 52242, United StatesValerie PUIG-ANTICH - Department of Pharmacology and the Molecular Biology Graduate Program, The University of Iowa, College of Medicine, Iowa City, Iowa 52242, United StatesChandrashekhar KORGAONKAR - Department of Pharmacology and the Molecular Biology Graduate Program, The University of Iowa, College of Medicine, Iowa City, Iowa 52242, United StatesAlex EAPEN - Department of Pharmacology and the Molecular Biology Graduate Program, The University of Iowa, College of Medicine, Iowa City, Iowa 52242, United StatesDawn E QUELLE - Department of Pharmacology and the Molecular Biology Graduate Program, The University of Iowa, College of Medicine, Iowa City, Iowa 52242, United States
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.61(7), pp.3145-3150
- Publisher
- American Association for Cancer Research; Philadelphia, PA
- PMID
- 11306500
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 2001
- Academic Unit
- Pathology; Neuroscience and Pharmacology
- Record Identifier
- 9984040586702771
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