Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen
Aniline exposure is associated with toxicity to the spleen leading to splenomegaly, hyperplasia, fibrosis and a variety of sarcomas of the spleen on chronic exposure. In earlier studies, we have shown that aniline exposure leads to iron overload, oxidative stress and activation of redox-sensitive transcription factors, which could regulate various genes leading to a tumorigenic response in the spleen. However, molecular mechanisms leading to aniline-induced cellular proliferation in the spleen remain largely unknown. This study was, therefore, undertaken on the regulation of G1 phase cell cycle proteins (cyclins), expression of cyclin-dependent kinases (CDKs), phosphorylation of retinoblastoma protein (pRB) and cell proliferation in the spleen, in an experimental condition preceding a tumorigenic response. Male SD rats were treated with aniline (0.5 mmol/kg/day via drinking water) for 30 days (controls received drinking water only), and splenocyte proliferation, protein expression of G1 phase cyclins, CDKs and pRB were measured. Aniline treatment resulted in significant increases in splenocyte proliferation, based on cell counts, cell proliferation markers including proliferating cell nuclear antigen (PCNA), nuclear Ki67 protein (Ki67) and minichromosome maintenance (MCM), MTT assay and flow cytometric analysis. Western blot analysis of splenocyte proteins from aniline-treated rats showed significantly increased expression of cyclins D1, D2, D3 and E, as compared to the controls. Similarly, real-time PCR analysis showed significantly increased mRNA expression for cyclins D1, D2, D3 and E in the spleens of aniline-treated rats. The overexpression of these cyclins was associated with increases in the expression of CDK4, CDK6, CDK2 as well as phosphorylation of pRB protein. Our data suggest that increased expression of cyclins, CDKs and phosphorylation of pRB protein could be critical in cell proliferation, and may contribute to aniline-induced tumorigenic response in the spleen.
- OSTI ID:
- 21535218
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 250, Issue 2; Other Information: DOI: 10.1016/j.taap.2010.10.026; PII: S0041-008X(10)00419-9; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANILINE
ANTIGENS
CELL CYCLE
CELL PROLIFERATION
CHRONIC EXPOSURE
DRINKING WATER
GENES
MESSENGER-RNA
PHOSPHORYLATION
PHOSPHOTRANSFERASES
POLYMERASE CHAIN REACTION
PROLIFERATION
RATS
SPLEEN
SPLENOMEGALY
TOXICITY
TRANSCRIPTION FACTORS
AMINES
ANIMALS
AROMATICS
BODY
CHEMICAL REACTIONS
ENZYMES
GENE AMPLIFICATION
HYDROGEN COMPOUNDS
MAMMALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PHOSPHORUS-GROUP TRANSFERASES
PROTEINS
RNA
RODENTS
SYMPTOMS
TRANSFERASES
VERTEBRATES
WATER