G1 arrest by p16INK4A uncouples growth from cell cycle progression in leukemia cells with deregulated cyclin E and c-Myc expression.

Abstract

The cell cycle inhibitor p16(INK4A) is frequently inactivated in acute lymphoblastic T-cell leukemia (T-ALL). We analyzed mechanisms and consequences of p16(INK4A) reconstitution in T-ALL cells lacking this tumor suppressor. CCRF-CEM cells with tetracycline-regulated p16(INK4A) expression underwent stable G1-phase cell cycle arrest for 72 h followed by massive apoptosis. p16(INK4A) expression caused pRB hypophosphorylation and repression of certain E2F target genes. Interestingly, cyclin E and c-Myc were not affected, suggesting pRB/E2F-independent expression of these E2F targets. Cyclin E/CDK2, however, was inactive due to stabilization and redistribution of p27(Kip1) from CDK4/CDK6 to CDK2. Analyses of c-Myc target genes suggested that c-Myc was transcriptionally inactive, which correlated with hypophosphorylation of the c-Myc inhibitor p107. Thus, p16(INK4A), although unable to repress the expression of deregulated cyclin E and c-Myc, functionally inactivated these potential oncogenes. p16(INK4A)-arrested cells showed morphologic changes, induction of T-cell-specific surface markers and repression of telomerase activity, suggesting differentiation. Moreover, p16(INK4A) reconstitution was associated with increased cellular volume, normal protein synthesis rates and elevated ATP levels. Taken together, p16(INK4A) reconstitution in p16(INK4A)-deficient T-ALL cells induced cell cycle arrest in the presence of cyclin E and c-Myc expression, uncoupled growth from cell cycle progression and caused a sequential process of growth, differentiation and apoptosis.

• Authors: M J Ausserlechner, P Obexer, S Geley, R Kofler
• Journal: Leukemia (Leukemia) Vol. 19 Issue 6 Pg. 1051-7 (Jun 2005) ISSN: 0887-6924 [Print] England
• PMID: 15800668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Cyclin E
• Cyclin-Dependent Kinase Inhibitor p16
• Nuclear Proteins
• RBL1 protein, human
• Retinoblastoma-Like Protein p107
• Telomerase

Topics

• Apoptosis (physiology)
• Biomarkers, Tumor
• Cell Differentiation (physiology)
• Cell Division (physiology)
• Child
• Cyclin E (genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• G1 Phase (physiology)
• Gene Expression Regulation, Leukemic
• Genes, myc (physiology)
• Humans
• Nuclear Proteins (genetics, metabolism)
• Phosphorylation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (metabolism, pathology, physiopathology)
• Retinoblastoma-Like Protein p107
• T-Lymphocytes (pathology, physiology)
• Telomerase (metabolism)
• Transcriptional Activation (physiology)