Heat Shock Protein 90 Stabilizes Nucleolin to Increase mRNA Stability in Mitosis

Abstract

Background:Nucleolin is an RNA-binding protein that regulates RNA stability. Results: CDK1 phosphorylates nucleolin at Thr-641/707 to stabilize nucleolin in a heat shock protein 90-dependent manner. Conclusion: Nucleolin stabilized by Hsp90 contributes to lung tumorigenesis by increasing the level of many tumor-related mRNAs during mitosis. Significance: Cancer cells exploit the increase in Hsp90 to maintain nucleolin stability and subsequently to increase the nucleus mRNA levels present in the cell nucleus, which might benefit tumorigenesis.

Anti-cancer activity of withaferin A in B-cell lymphoma

“…2A) which could be due to a decrease in CDK4, a kinase required for G 1 progression. 18,31,32 These results support the hypothesis that WA targets the activity of Hsp90 in DLBCL, resulting in decreased expression of its client proteins that include CDK1 and CDK4, 33,34 which affect different phases of the cell cycle, but does not have a significant effect on non-client proteins of Hsp90 including CDK2 or cyclin A1 (Fig. S1).…”

RNA-binding protein nucleolin in disease

“…Oxidative stress increased the cleavage of nucleolin and lowered the levels of intact nucleolin; in laryngeal squamous cell carcinoma (LSCC), the 70-kDa heat shock protein (HSP70) inhibited the cleavage and degradation of nucleolin, likely impacting on LSCC radiotherapy resistance, and in lung cancer cells, HSP90 protected nucleolin stability during mitosis. 76,77 The self-cleaving activity of nucleolin was significantly decreased in dividing T lymphocytes, likely due to the increased concentration of proteolytic inhibitors in the nuclei of these cells. 78 LYAR, a zinc finger nucleolar oncoprotein that is highly expressed in undifferentiated embryonic stem cells (ESCs), associated with nucleolin, prevented its self-cleavage and elevated nucleolin concentration.…”

“…In keeping with this broad influence on cancer gene expression programs, a subset of nucleolin-associated mRNAs encoding tumor-related proteins were recently identified in mitotic cells. 21,77 Degradation of the extracellular matrix (ECM) is essential for angiogenesis and metastasis. 124,125 Since nucleolin associates with MMP9 mRNA and enhances its translation, it may help cancer cells to invade and metastasize.…”

A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis

“…On the plasma membrane, NCL serves as a binding protein for a variety of ligands implicated in cancer pathogenesis, representing a potential strategic target for effective and non-toxic cancer therapy [12-15]. In the cytoplasm, NCL functions as a mRNA stabilizer [i.e., BCL-2 [16], CD154 [17], IL-2 [18] and many other tumor-related mRNAs [19]] and participates in microRNA biogenesis (i.e., miR15 , miR16 ) [20]. In the nucleolus, NCL acts as a transcriptional factor, by directly binding to target gene promoters [21-23] or chaperoning with histone [24] to control gene expression, arguing for the complexity and the significance of NCL functions in cancer.…”