RbAp48 is a target of nuclear factor-kappaB activity in thyroid cancer.

Abstract

CONTEXT:

We have recently shown that nuclear factor (NF)-kappaB activity is constitutively elevated in anaplastic human thyroid carcinomas. The inhibition of NF-kappaB in the anaplastic thyroid carcinoma cell line (FRO) leads to increased susceptibility to apoptosis induced by chemotherapeutic drugs and to the block of oncogenic activity.

OBJECTIVES:

To understand better the molecular mechanisms played by NF-kappaB in thyroid oncogenesis, we performed a differential proteomic analysis between FRO transfected with a superrepressor form of inhibitor of kappaBalpha (IkappaBalphaM) and the parental counterpart (FRO Neo cells).

RESULTS:

Differential proteomic analysis revealed that the retinoblastoma-associated protein 48 (RbAp48) is down-regulated in the absence of functional NF-kappaB. Immunohistochemical analysis of normal and pathological human thyroid specimens confirmed that RbAp48 is strongly overexpressed in primary human carcinomas. Reduction of RbAp48 expression using small interfering RNA determined the suppression of tumorigenicity, very likely due to the decrease of their growth rate rather than to an increased susceptibility to apoptosis. In addition, we showed that NF-kappaB, at least in part, transcriptionally controls RbAp 48. A functional NF-kappaB consensus sequence was located within the promoter region of RbAp48 human gene, and embryonic fibroblasts isolated from the p65 knockout mouse (murine embryonic fibroblasts p65-/-) showed decreased expression of RbAp48.

CONCLUSION:

Our results show that RbAp48 is a NF-kappaB-regulated gene playing an important role in thyroid cancer cell autonomous proliferation.

• Authors: Francesco Pacifico, Michele Paolillo, Gennaro Chiappetta, Elvira Crescenzi, Simona Arena, Andrea Scaloni, Mario Monaco, Carlo Vascotto, Gianluca Tell, Silvestro Formisano, Antonio Leonardi
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 92 Issue 4 Pg. 1458-66 (Apr 2007) ISSN: 0021-972X [Print] United States
• PMID: 17244783 (Publication Type: Journal Article)

Chemical References

• Carrier Proteins
• DNA, Neoplasm
• NF-kappa B
• Nuclear Proteins
• RBBP4 protein, human
• RNA, Small Interfering
• Retinoblastoma-Binding Protein 4
• Thymidine

Topics

• Blotting, Northern
• Carrier Proteins (genetics)
• Consensus Sequence
• DNA, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Mass Spectrometry
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics)
• Promoter Regions, Genetic
• RNA, Small Interfering (genetics)
• Retinoblastoma-Binding Protein 4
• Thymidine (metabolism)
• Thyroid Neoplasms (metabolism)