Control of mRNA translation and stability in haematopoietic cells: The function of hnRNPs K and E1/E2

Ostareck-Lederer, Antje; Ostareck, Dirk H.

doi:10.1016/j.biolcel.2004.03.010

Cited by 90 publications

(75 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TP expression in the cancer cells of NPC patients has been significantly correlated with cytoplasmic accumulation of hnRNP K (Chen et al, 2008), which has been associated with the posttranscriptional control of CURE-containing mRNA (Bomsztyk et al, 2004;Ostareck-Lederer and Ostareck, 2004;Wang et al, 2006). To assess the possible role of hnRNP K in regulating TP mRNA stability under serum deprivation conditions, we examined whether hnRNP K knockdown affected luciferase activity from a CURE-containing reporter construct.…”

Section: Tp Is Strongly Induced In Serum-deprived Npc Cellsmentioning

confidence: 99%

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Liu

et al. 2009

Oncogene

View full text Add to dashboard Cite

The cytoplasmic level of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is significantly correlated with the elevated expression of thymidine phosphorylase (TP), and high levels of both proteins are predictive of a poor prognosis in nasopharyngeal carcinoma (NPC). We herein show that TP is highly induced by serum deprivation in NPC cells, and that this is due to an increase in the halflife of the TP mRNA, as shown by nuclear run-on and actinomycin D assays. We further show that the CU-rich element of the TP mRNA directly interacts with hnRNP K, as demonstrated by immunoprecipitation RT-PCR assays, and the nucleus-to-cytoplasm translocation of hnRNP K. Blockade of hnRNP K expression reduces TP expression, suggesting that hnRNP K acts in the upregulation of TP. Mechanistically, both MEK inhibitor and the hnRNP K ERK-phosphoacceptor-site mutant decrease cytoplasmic accumulation of hnRNP K, suggesting that ERK-dependent phosphorylation is critical for TP induction. Furthermore, we found that hnRNP Kmediated TP induction allows NPC cells to resist hypoxia-induced apoptosis. Our results collectively establish the regulation and role of ERK-mediated cytoplasmic accumulation of hnRNP K as an upstream modulator of TP, suggesting that hnRNP K may be an attractive candidate as a future therapeutic target for cancer.

show abstract

Section: Tp Is Strongly Induced In Serum-deprived Npc Cellsmentioning

confidence: 99%

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Liu

et al. 2009

Oncogene

View full text Add to dashboard Cite

show abstract

“…Extracellular signal-regulated kinase (ERK)-dependent serine phosphorylation mediates the cytoplasmic accumulation of hnRNP K (19). In the cytoplasm, hnRNP K functions as a translational regulator of specific mRNAs, such as c-myc mRNA (12), renin mRNA (44,45), human papillomavirus type 16 L2 capsid protein mRNA (6), and reticulocyte-15-lipoxygenase (r15-LOX) mRNA (36)(37)(38). The mechanism of hnRNP K action has been extensively studied in r15-LOX mRNA translational regulation.…”

mentioning

confidence: 99%

“…The silencing complex blocks 80S ribosome assembly (36,37). In mature reticulocytes, r15-LOX mRNA translation becomes activated (38). Interestingly, hnRNP K, but not hnRNP E1, activates c-Src specifically and is phosphorylated by the kinase (39).…”

mentioning

confidence: 99%

Deciphering the Cross Talk between hnRNP K and c-Src: the c-Src Activation Domain in hnRNP K Is Distinct from a Second Interaction Site

Adolph

Flach

Mueller

et al. 2007

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

The protein tyrosine kinase c-Src is regulated by two intramolecular interactions. The repressed state is achieved through the interaction of the Src homology 2 (SH2) domain with the phosphorylated C-terminal tail and the association of the SH3 domain with a polyproline type II helix formed by the linker region between SH2 and the kinase domain. hnRNP K, the founding member of the KH domain protein family, is involved in chromatin remodeling, regulation of transcription, and translation of specific mRNAs and is a target in different signal transduction pathways. In particular, it functions as a specific activator and a substrate of the tyrosine kinase c-Src. Here we address the question how hnRNP K interacts with and activates c-Src. We define the proline residues in hnRNP K in the proline-rich motifs P2 (amino acids [aa] 285 to 297) and P3 (aa 303 to 318), which are necessary and sufficient for the specific activation of c-Src, and we dissect the amino acid sequence (aa 216 to 226) of hnRNP K that mediates a second interaction with c-Src. Our findings indicate that the interaction with c-Src and the activation of the kinase are separable functions of hnRNP K. hnRNP K acts as a scaffold protein that integrates signaling cascades by facilitating the cross talk between kinases and factors that mediate nucleic acid-directed processes.

show abstract

“…Both recognize sequences harboring tandem pyrimidine-rich elements with poly(C) stretches within the 3Ј UTRs and can confer increased stability (23)(24)(25) and in some cases translational silencing (25). In addition to stabilizing mRNAs, PCBP2 has been implicated in regulating transcription (26) and in enhancing translation through a cap-independent mechanism involving an internal ribosome entry site in the 5Ј UTR (IRES) (15).…”

Section: Discussionmentioning

confidence: 99%

A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteracting environmental stress

Ghosh¹,

Srivastava²,

Xu³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

When SIN1 (MAPKAP1) was used as the bait in a two-hybrid screen of a human bone marrow cDNA library, its most frequent partner was poly(rC) binding protein 2 (PCBP2/hnRNP-E2), which associates with the N-terminal domain of SIN1 and can be coimmunoprecipitated with SIN1 and the cytoplasmic domain of the IFN receptor IFNAR2 from HeLa cells. SIN1, but not PCBP2, also associates with the receptors that bind TNF␣. PCBP2 is known to bind pyrimidinerich repeats within the 3 UTR of mRNAs and has been implicated in control of RNA stability and translation and selective capindependent transcription. RNAi silencing of either SIN1 or PCBP2 renders cells sensitive to basal and stress-induced apoptosis. Stress in the form of TNF␣ and H2O2 treatments rapidly raises the cell content of SIN1 and PCBP2, an effect reversible by inhibiting MAPK14. A meta analysis of human microarray information with an algorithm that discerns similarities in gene-regulatory profiles shows that SIN1 and PCBP2 are generally coregulated with large numbers of genes implicated in both cell survival and death and in cellular stress responses, including RNA translation and processing. We predict that SIN1 is a scaffold protein that organizes antiapoptotic responses in stressed cells, whereas PCBP2, its binding partner, provides for the selective expression of cell survival factors through posttranslational events.apoptosis ͉ interferon ͉ stress kinase-interacting protein 1 ͉ yeast two-hybrid assay W hen faced with environmental stressors such as reactive oxygen species, inflammatory shock, or viral infection, cells may react by either boosting protective mechanisms or undergoing programmed cell death. A delicate balance is maintained between pathways that promote survival or death, and this balance can be affected by a number of cytokines, including members of the IL, IFN, and TNF families (1). The type 1 IFN in particular have the ability to promote (2, 3) or prevent (4) cell death depending on the circumstances. Exposure of cells to stress induces compensatory activation of multiple intracellular signaling pathways, among which is the one controlled by p38 MAPK (MAPK14), also known as stress-activated protein kinase (5).We previously used yeast two-hybrid genetic screens to identify stress kinase-interacting protein 1 (SIN1; MAPKAP1) as a factor that associates with the IFN receptor subunit IFNAR2 (6). Cells in which the SIN1 gene has been ablated or where gene expression had been knocked down by RNAi silencing are susceptible to stress (7,8). SIN1 is represented as a single gene in all metazoan species and fungi so far examined, is highly conserved in vertebrates, and is expressed in most, if not all, tissues of the mouse (6). Despite this ubiquity, it has until recently been poorly studied, and its mechanisms of action remain unclear. It was originally described as a gene product that modulated RAS function in Saccharomyces cerevisiae (9). Later, a yeast two-hybrid screen of a Schizosaccharomyces pombe cDNA library identified an apparent ortholog of t...

show abstract

Control of mRNA translation and stability in haematopoietic cells: The function of hnRNPs K and E1/E2

Cited by 90 publications

References 47 publications

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells

Deciphering the Cross Talk between hnRNP K and c-Src: the c-Src Activation Domain in hnRNP K Is Distinct from a Second Interaction Site

A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteracting environmental stress

Contact Info

Product

Resources

About