Early Increase in Cyclin-D1 Expression and Accelerated Entry of Mouse Hepatocytes into S Phase after Administration of the Mitogen 1,4-Bis[2-(3,5-Dichloropyridyloxy)] Benzene

Ledda-Columbano, Giovanna M.; Pibiri, Monica; Loi, Roberto; Perra, Andrea; Shinozuka, Hisashi; Columbano, Amedeo

doi:10.1016/s0002-9440(10)64709-8

Cited by 94 publications

(78 citation statements)

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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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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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“…Recent studies have suggested that cyclin D1 is markedly up-regulated by the chemical mitogen TCPOBOP as well as triiodothyronine in vivo, whereas cyclin D3 shows little change in expression. 57,58 This suggests that mitogenic nuclear receptors may induce hepatocyte proliferation via direct induction of cyclin D1, but have little effect on cyclin D3. These data further argue that cyclins D1 and D3 play a fundamentally distinct role in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cyclins D1 and D3 in hepatocyte proliferation

et al. 2002

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Substantial evidence suggests that cyclin D1 plays a pivotal role in the control of the hepatocyte cell cycle in response to mitogenic stimuli, whereas the closely related protein cyclin D3 has not been extensively evaluated. In the current study, we examined the regulation of cyclins D1 and D3 during hepatocyte proliferation in vivo after 70% partial hepatectomy (PH) and in culture. In contrast to cyclin D1, which was nearly undetectable in quiescent liver and substantially up-regulated after PH, cyclin D3 was constitutively expressed and induced only modestly. In the regenerating liver, the concentration of cyclin D3 was only about 10% of that of cyclin D1. Cyclin D1 formed complexes primarily with cyclin-dependent kinase 4 (cdk4), which were markedly activated in the regenerating liver and readily sequestered the cell cycle inhibitory proteins, p21 and p27. Cyclin D3 bound to both cdk4 and cdk6. Cyclin D3/cdk6 activity was readily detectable in quiescent liver and changed little after PH, and this complex appeared to play a minor role in sequestering p21 and p27. In cultured hepatocytes, epidermal growth factor or insulin had little effect, but the combination of these agents substantially induced cyclin D1 and cell cycle progression. Inhibition of Mek1 or phosphoinositide 3-kinase markedly inhibited cyclin D1 expression and replication. In contrast, cyclin D3 was expressed in the absence of mitogens and was only modestly affected by these manipulations. In addition, growth-inhibitory extracellular matrix conditions inhibited cyclin D1 but not cyclin D3 expression. In conclusion, these results support the concept that cyclin D1 is critically regulated by extracellular stimuli that control proliferation, whereas cyclin D3 is regulated through different pathways and plays a distinct role in the liver. (HEPATOLOGY 2002;36:30-38.) P rogression through the cell cycle is regulated by the activity of protein kinase complexes consisting of cyclins and cyclin-dependent kinases (cdk), which are activated at distinct stages of proliferation. 1-3 During G1 phase, mitogens up-regulate the D-type cyclins, which form complexes with cdk4 and cdk6 that phosphorylate the retinoblastoma protein (Rb) and the related p107 and p130 proteins. The three D-type cyclins (D1, D2, and D3) display significant homology, suggesting that they may perform overlapping functions. 4,5 This concept is supported by studies showing that cyclin D1 or D2 knockout mice are viable and show relatively limited phenotypic effects. 6-8 On the other hand, the expression patterns of the D-type cyclins vary widely in different cell types, suggesting that they have distinct functions in specific tissues. Although cyclins D1 and D2 clearly regulate cell proliferation, the role of cyclin D3 has not been well characterized. Cyclin D3 is implicated in cell cycle control in some types of cells, but it is also widely expressed in nonreplicating mammalian tissues, indicating that it plays a role in quiescent cells. 9,10 Indeed, cyclin D3 is up-regulated during te...

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“…We have recently shown that the hepatocyte response to T3 is associated with a rapid induction of cyclin D1 and an accelerated entry into the S phase (Pibiri et al 2001). Based on the finding that an early induction of cyclin D1 was found following treatment with other ligands with mitogenic activity (Ledda-Columbano et al 2000a), it has been proposed that cyclin D1 is a direct target gene of the transcriptional activity of these receptors (Ledda-Columbano & Columbano 2003).…”

Section: Introductionmentioning

confidence: 99%

Induction of pancreatic acinar cell proliferation by thyroid hormone

Ledda-Columbano¹,

Perra²,

Pibiri³

et al. 2005

Journal of Endocrinology

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Thyroid hormone is known to elicit diverse cellular and metabolic effects in various organs, including mitogenesis in the rat liver. In the present study, experiments were carried out to determine whether thyroid hormone is able to stimulate cell proliferation in another quiescent organ such as the pancreas. 3,5,3 --tri-iodothyronine (T3) added to the diet at a concentration of 4 mg/kg caused a striking increase in nuclear bromodeoxyuridine (BrdU) incorporation of rat acinar cells 7 days after treatment (the labeling index was 46·7% in T3-treated rats vs 7·1% in controls). BrdU incorporation was limited to the acinar cells, with duct cells and islet cells being essentially negative. The increase in DNA synthesis was accompanied by the presence of several mitotic figures. Histological examination of the pancreas did not exhibit any sign of T3-induced toxicity. Determination of the apoptotic index, measurement of the serum levels of -amylase and lipase, and glycemia determination did not show any increase over control values, suggesting that the enhanced proliferation of acinar cells was a direct effect induced by T3 and not a regenerative response consequent to acinar or -cell injury. Additional experiments showed that DNA synthesis was induced as early as 2 days after T3 treatment (the labeling index was 9·4 vs 1·9% in controls) and was associated with increased protein levels of cyclin D1, cyclin A and proliferating cell nuclear antigen, with no substantial differences in the expression of the cyclindependent kinase inhibitor p27. The mitogenic effect of T3 on the pancreas was not limited to the rat, since extensive acinar cell proliferation was also observed in the pancreas of mice treated with T3 for 1 week (the labeling index was 28% in T3-treated mice vs 1·8% in controls). Treatment with three other ligands of nuclear receptors, ciprofibrate, all-trans retinoic acid and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, induced little or no pancreatic cell proliferation. These results demonstrated that T3 is a powerful inducer of cell proliferation in the pancreas and suggested that pancreatic acinar cell proliferation by selected agents may have potential for therapeutic use.

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Early Increase in Cyclin-D1 Expression and Accelerated Entry of Mouse Hepatocytes into S Phase after Administration of the Mitogen 1,4-Bis[2-(3,5-Dichloropyridyloxy)] Benzene

Cited by 94 publications

References 50 publications

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

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

Differential regulation of cyclins D1 and D3 in hepatocyte proliferation

Induction of pancreatic acinar cell proliferation by thyroid hormone

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