Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases

Albrecht, Jeffrey H.; Hoffman, J S; Kren, Betsy T.; Steer, C J

doi:10.1152/ajpgi.1993.265.5.g857

Cited by 51 publications

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“…No significant differences could be noticed between the two chemically modified sequences and no changes with all control mutated sequences. In parallel, we looked at cell cycle markers expressions of cyclin D1 (Figure 5a) and Cdk1 (Figure 5b), two markers which are expressed, respectively, at late G 1 and S phase in normal hepatocytes and in HCC (Albrecht et al, 1993(Albrecht et al, , 1995Ito et al, 1998;Rescan et al, 2001). Our results showed that cyclin D1 inhibition was partially inhibited in transfected cells.…”

Section: Erk2 Targeting Inhibits Tumor Growthmentioning

confidence: 77%

“…In primary culture of normal hepatocytes, expression of Cdk1, one marker of G 1 /S phase transition, is regulated by the MEK/ERK pathway (Albrecht et al, 1993;Rescan et al, 2001;Huynh et al, 2003). Therefore, we looked at the regulation of this protein in transformed FAO cells and showed that Cdk1 expression was significantly blocked when cells were treated with U0126 ( Figure 1b).…”

Section: Proliferation Of Hepatocarcinoma Cells Is Mediated By the Mementioning

confidence: 99%

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RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

et al. 2008

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The MAPK MEK/ERK pathway is often upregulated in cancer cells and represents an attractive target for development of anticancer drugs. Only few data concerning the specific functions of ERK1 and 2 are reported in the literature. In this report, we investigated the specific role of ERK1 and 2 in liver tumor growth both in vitro and in vivo. DNA synthesis and cells in S phase analysed by flow cytometry, correlated with strong inhibition of Cdk1 and cyclin E levels, are strongly reduced after exposure to the MEK inhibitor, U0126. We obtained a significant reduction of colony formation in soft agar assays and a reduction in the size of tumor xenografts in nude mice treated with U0126. Then, we could specifically abolished ERK1 or 2 expression by small-interfering RNA (siRNA) and demonstrated that ERK2 knockdown but not ERK1 interferes with the process of replication. Moreover, we found that colony formation and tumor growth in vivo were significantly inhibited by targeting ERK2 using stable chemically modified siRNA. Taken together, our results emphasize the importance of the MEK/ERK pathway in liver cancer cell growth in vitro and in vivo and argue for a crucial role of ERK2 in this regulation.

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Section: Erk2 Targeting Inhibits Tumor Growthmentioning

confidence: 77%

Section: Proliferation Of Hepatocarcinoma Cells Is Mediated By the Mementioning

confidence: 99%

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

et al. 2008

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“…As to the liver, enhanced expression of cyclin D1 before the onset of DNA synthesis has been reported in liver regeneration after two-thirds partial hepatectomy 7,24,34,35 and represents one of the earliest events following treatment with chemicals that have mitogenic activity for rodent liver, especially ligands of nuclear receptors of the steroid/thyroid receptor superfamily 7,24 ; however, the exact role and relevance of cyclin D1 in hepatocyte proliferation in vivo is not clear. The present results clearly show that, although lack of cyclin D1 might delay the entry into S phase for a relatively short time, this cyclin is not essential for liver growth and hepatocyte proliferation.…”

Section: Resultsmentioning

confidence: 99%

Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli

et al. 2002

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Cyclin D1 is considered to play a critical role in the progression from G1 to S phase of the cell cycle, and its overexpression is seen in many human tumors. However, previous studies in cell lines have shown that cyclin D1 is not sufficient to trigger cell replication. To directly test the role of cyclin D1 in the progression of the cell cycle, we have examined the proliferative response of hepatocytes to the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in mice with homozygous disruption of the cyclin D1 gene. We found that 24 hours after administration of TCPOBOP, the number of bromodeoxyuridine (BrdU)-positive hepatocytes was significantly reduced in cyclin D1 ؊/؊ (labeling index was 1.9% in knockout mice vs. 9.7% of heterozygous mice); however, no difference in the number of proliferating hepatocytes was found 36 or 72 hours after treatment (labeling index was 16% and 43% in cyclin D1 ؊/؊ mice vs. 20% and 41% of heterozygous mice), indicating that lack of cyclin D1 may transiently delay entry into S phase but is not sufficient to inhibit the response of hepatocytes to mitogenic stimuli. The results also show that although there was no difference in hepatic protein levels of cyclin D2 and D3 between untreated cyclin D1 ؊/؊ and cyclin D1 ؉/؊ mice, messenger RNA (mRNA) and protein levels of cyclin E were much higher in the former. In conclusion, our results show that cyclin D1 is not essential for liver development and hepatocyte proliferation induced by mitogenic stimuli and suggest that overexpression of cyclin E may compensate for the lack of cyclin D1. (HEPATOLOGY 2002;36: 1098-1105.)T he liver has the capacity to regenerate after surgical or chemical removal of part of its cellular mass. During the last decade, much new information has become available on the events that may initiate liver regeneration. 1 Several converging lines of evidence have proposed that tumor necrosis factor ␣ and interleukin 6 are important components of the early signaling pathways leading to regeneration. 2-4 Hepatocytes, however, can be stimulated to proliferate by treatment with a variety of agents such as thyroid hormone, peroxisome proliferators, lead nitrate, and others that do not cause tissue injury but rather an excess of cells (primary mitogens). 5 We have previously shown that hepatocyte proliferation induced by several mitogens, especially ligands of nuclear receptors of the steroid/thyroid receptor superfamily, occurs in a tumor necrosis factor ␣-and interleukin 6 -independent pathway and in the absence of changes in immediate-early gene expression or activation of transcription factors such as nuclear factor B, STAT3, or AP-1. [6][7][8] In the same studies, it was shown that at least 3 different hepatomitogens, thyroid hormone, nafenopin, and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), induce a very rapid increase of cyclin D1 expression and an accelerated entry of hepatocytes into S phase, suggesting that cyclin D1 may be a common critical target gene in this type of proliferation ...

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“…The expression of cyclins in the regenerating liver has been studied extensively (Lu et al 1992;Albrecht et al 1993;Loyer et al 1994;Michalopoulos and De Frances 1997). The delay in hepatocyte proliferation seen in CREM-deficient mice (Fig.…”

Section: Deregulation Of Cyclinsmentioning

confidence: 99%

Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

Servillo¹,

Fazia²,

Sassone–Corsi³

1998

Genes Dev.

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The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM −/− mice. There is a reduction in DNA synthesis, in the number of mitosis and of phosphorylated histone H3-positive cells. The post-PH proliferation peak is delayed by 10 hr, indicating an altered hepatocyte cell cycle. Expression of cyclins A, B, D1, E, and cdc2, of c-fos and tyrosine aminotransferase is deregulated. CREM mutation results in delayed S-phase entry, impairing the synchronization of proliferation. Received September 10, 1998; revised version accepted October 15, 1998. The liver is one of the most important organs for homeostasis in mammals. Among its properties is the remarkable ability to regenerate following partial hepatectomy (Michalopoulos 1990;Fausto 1994). As much as 70% of the liver can be surgically removed and hepatocytes will proliferate to fully regenerate the original cell mass. The initial rounds of cell division are synchronous, and the first DNA replication occurs within 24 hr of surgery in the rat. The regeneration process is completed within 10-15 days (Bucher 1963).A number of hormones, growth factors, and cytokines and their coupled signal transduction pathways have been implicated in governing hepatocyte proliferation, but the precise orchestration of these factors is poorly understood (Diehl and Rai 1996;Michalopoulos and De Frances 1997). In particular, cytokines IL-6 and TNF have been implicated in initiating hepatocyte DNA synthesis during regeneration (Fausto et al. 1995;Cressman et al. 1996;Yamada et al. 1997), whereas the DNA-binding activity of the downstream transcription factors Stat3 and NF-B increases during the first hours following hepatectomy (Taub 1996).A characteristic feature of liver regeneration is the dramatic increase in intracellular cAMP levels during the hepatocyte proliferation process, although its significance has remained elusive (Diehl et al. 1992). cAMP peaks during the first hours following partial hepatectomy, whereas elevated levels of cAMP also correlate with the proliferation of liver cell at birth (Diehl and Rai 1996). These notions underscore the critical role that must be played by cAMP-responsive transcription factors in liver regeneration.Transcription factors coupled to cAMP signaling constitute a family of closely related bZIP proteins, either activators or repressors, binding to cAMP-responsive promoter elements (CREs) located within the regulatory regions of cAMP-inducible genes (Sassone-Corsi 1995; Montminy 1997). The factors CREB (CRE-binding protein), CREM (CRE modulator), and ATF-1 (activator transcription factor 1) are turned into activators by phosphorylation at a serine residue (Ser-133 in CREB; Ser-117 in CREM) (Gonzalez and Montminy 1989;De Groot et al. 1993) elicited by PKA and other kinases (SassoneCorsi 1995;Montminy 1997). Interestingly, a C...

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Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases

Cited by 51 publications

References 0 publications

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

Loss of cyclin D1 does not inhibit the proliferative response of mouse liver to mitogenic stimuli

Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver

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