Involvement of the p38 mitogen‐activated protein kinase cascade in hepatocellular carcinoma

Iyoda, Kenya; Sasaki, Yutaka; Horimoto, Masayoshi; Toyama, Takashi; Yakushijin, Takayuki; Sakakibara, Mitsuru; Takehara, Tetsuo; Fujimoto, Jiro; Hori, Masatsugu; Wands, Jack R.; Hayashi, Norio

doi:10.1002/cncr.11425

Cited by 142 publications

(106 citation statements)

References 87 publications

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“…Activation of p38 in the rat fibroblasts is known to be associated with Myc-dependent apoptosis when exposed to cisplatin (34). Furthermore, a significantly lowered activity of p38 and MKK6 has been reported in hepatocellular carcinoma compared with normal tissue, suggesting the importance of this pathway in controlling unrestricted cellular proliferation (65). Although Rac1 and cdc42 belong to the same family of Rho GTPase, we have observed the involvement of only Rac1 in activation of p38 pathway.…”

Section: C-fos As Mediator Of C-myc-induced Apoptosismentioning

confidence: 48%

c-Fos Is a Mediator of the c-Myc-induced Apoptotic Signaling in Serum-deprived Hepatoma Cells via the p38 Mitogen-activated Protein Kinase Pathway

Kalra¹,

Kumar

2004

Journal of Biological Chemistry

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The proto-oncogene c-myc encodes a transcription factor that plays a pivotal role in cell proliferation, differentiation, and apoptosis. The signaling mechanism of c-Myc-induced apoptosis was investigated on the human hepatoma Huh7 cells under growth factor-deprived conditions. The apoptotic process did not involve p53. Rather it was dependent on the expression of c-Fos. Activation of caspases 3 and 9 and down-regulation of Bcl2 were observed in the apoptotic process, indicating it to be a mitochondria-dependent event. An increase in the p38 mitogen-activated protein kinase that was mediated by a Rac1-dependent and cdc42-independent pathway eventually leading to up-regulation of c-

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Section: C-fos As Mediator Of C-myc-induced Apoptosismentioning

confidence: 48%

c-Fos Is a Mediator of the c-Myc-induced Apoptotic Signaling in Serum-deprived Hepatoma Cells via the p38 Mitogen-activated Protein Kinase Pathway

Kalra¹,

Kumar

2004

Journal of Biological Chemistry

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“…On the contrary, p38 MAPK and p38 MAPK kinase (MKK3) have been shown to significantly inhibit mitogen-induced cyclin D1 expression in the constitutively active Raf-1 and estrogen receptor fusion protein stably expressed CCL39 cells (13). The association of human HCC with nearby normal tissues has been shown to reduce p38 MAPK and MKK6 activities especially in larger tumors (36). Moreover, it has been reported recently that p38 MAPK␣ suppresses liver cancer development by antagonizing the JNK-c-Jun pathway (14).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Heat Shock Protein 27 Represses Growth of Hepatocellular Carcinoma via Inhibition of Extracellular Signal-regulated Kinase

Matsushima‐Nishiwaki

Takai

Adachi

et al. 2008

Journal of Biological Chemistry

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Heat shock protein 27, one of the low molecular weight stress proteins, is recognized as a molecular chaperone; however, other functions have not yet been well established. Phosphorylated heat shock protein 27 levels inversely correlate with the progression of human hepatocellular carcinoma. This study shows that phosphorylated heat shock protein 27 interferes with cell growth of the hepatocellular carcinoma-derived HuH7 cells in the presence of the proinflammatory cytokine, tumor necrosis factor-␣, via inhibition of the sustained activation of the extracellular signal-regulated kinase signal pathway. The activities of Raf/extracellular signal-regulated kinase and subsequent activator protein-1 transactivation and the induction levels of cyclin D1 were lower in HuH7 cells transfected with phosphorylated heat shock protein 27 than those with unphosphorylated heat shock protein 27. Moreover, phosphorylated heat shock protein 27 up-regulated the levels of p38 mitogen-activated protein kinase and mitogen-activated protein kinase phosphatase-1, an inhibitory protein of extracellular signal-regulated kinase. These results indicate that phosphorylated heat shock protein 27 might suppress the extracellular signal-regulated kinase activity in the hepatocellular carcinoma cells via two separate pathways in an inflammatory state. The extracellular signal-regulated kinase activity is inversely correlated with phosphorylated heat shock protein 27 at serine 15 and also in human hepatocellular carcinoma tissues in vivo. Because the extracellular signal-regulated kinase signal pathway is a major proliferation signal of hepatocellular carcinoma, activator protein-1 activation is an early event in hepatocarcinogenesis. These findings strongly suggest that the control of the phosphorylated heat shock protein 27 levels could be a new therapeutic strategy especially to counter the recurrence of hepatocellular carcinoma.The mammalian small stress protein, heat shock protein (HSP) 2 27, is a widely expressed 27-kDa protein, and it is one of 10 members of the human low molecular weight HSP family. HSPs are classified into high molecular weight HSPs such as HSP70 and HSP90, and low molecular weight HSPs with molecular masses from 10 to 30 kDa based on their apparent molecular sizes. Low molecular weight HSPs have significant similarities in terms of amino acid sequences, known as the ␣-crystallin domain and WDPF motif (1, 2). The high molecular weight HSPs act as molecular chaperones in protein folding, oligomerization, and translocation (1). Although the functions of low molecular weight HSPs are not as well characterized as those of the high molecular weight HSPs, it is recognized that they may have chaperone activities (1). The functions of HSP27 are regulated by post-translational modifications such as phosphorylation (3, 4). Mouse HSP27 is phosphorylated at two sites (Ser-15 and Ser-82), whereas human HSP27 is phosphorylated at three sites (Ser-15, Ser-78, and Ser-82) (3). Ser-78 and Ser-82 of HSP27 are adjacent to the amino-termin...

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“…Thus, alterations of p38 SAPK activity might have a role in oncogenesis by impairing checkpoints, apoptosis or/ and cell proliferation. Although not much information has been reported about the levels and activities of p38 SAPK proteins in tumors, a recent report indicates that the activity of p38 SAPK2 is attenuated in a series of human hepatocarcinoma samples and this decrease in the activity correlates with a higher tumor size, suggesting that it leads to an unrestricted cell growth (Iyoda et al, 2003). Taking into account these considerations recent reports focus attention on the relevance of p38 SAPK proteins as potential targets in cancer therapy (Morin and Huot, 2004;Olson and Hallahan, 2004).…”

Section: Discussionmentioning

confidence: 99%

P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation

et al. 2004

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Cyclin D3 plays a critical role in maturation of precursor T cells and their levels are tightly regulated during this process. Alteration of cyclin D3 levels has been proposed to be important in the development of different human cancers, including malignancies of the lymphoid system. Thus, we have analysed the mechanisms involved in the regulation of cyclin D3 levels. Our results indicate that cyclin D3 is degraded via proteasome and that Thr-283 is essential for its degradation. Wild-type cyclin D3 but not the Thr-283A mutant accumulated ubiquitylated forms after treatment with proteasome inhibitors. We also observed that different type of stresses promote the Thr-283-dependent in vivo degradation of cyclin D3. The analysis of the kinases involved in Thr-283 phosphorylation indicates that all the members of the p38 SAPK family of serine-threonine kinases are able to phosphorylate cyclin D3 at this specific site. Moreover, we found that the overexpression of p38a SAPK2 induce the decrease of cyclin D3 in vivo. These results indicate that p38 SAPK might be involved in the regulation of cyclin D3 levels and suggest that this mechanism is involved in the maturation of precursor T-cells. Alterations of this mechanism might be important for oncogenesis.

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Involvement of the p38 mitogen‐activated protein kinase cascade in hepatocellular carcinoma

Cited by 142 publications

References 87 publications

c-Fos Is a Mediator of the c-Myc-induced Apoptotic Signaling in Serum-deprived Hepatoma Cells via the p38 Mitogen-activated Protein Kinase Pathway

c-Fos Is a Mediator of the c-Myc-induced Apoptotic Signaling in Serum-deprived Hepatoma Cells via the p38 Mitogen-activated Protein Kinase Pathway

Phosphorylated Heat Shock Protein 27 Represses Growth of Hepatocellular Carcinoma via Inhibition of Extracellular Signal-regulated Kinase

P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation

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