286 Gene expression profile at the G1/S boundary of liver regeneration after partial hepatectomy in mice

Satyanarayana, A.; Buer, Jörn van; Manns, MP; Rudolph, K.L.

doi:10.1016/s0168-8278(04)90286-3

Cited by 3 publications

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“…We employed the well-established liver regeneration after partial hepatectomy (PH) as a model system (Fausto, 2000; Kountouras et al, 2001) to study the transcriptional activation of Cdk1 during in vivo cell cycle initiation and progression in the presence or absence of Cdk2. In response to PH, S phase initiation occurs at 24 hours, peaks at 48 hours, and the first round of replication is completed approximately at 72 hours (Fausto, 2000; Satyanarayana et al, 2004). We monitored the transcriptional activation of Cdk1 in regenerating livers of Cdk2 +/+ Cdk1 +/Cdk2KI and Cdk2 −/− Cdk1 +/Cdk2KI mice by β-galactosidase staining (Figure 6, A1-B4).…”

Section: Resultsmentioning

confidence: 99%

Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2

et al. 2008

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It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1Cdk2KI). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality,even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2-/-Cdk1+/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2-/-Cdk1+/Cdk2KI mice were sterile, similar to Cdk2-/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2-/-Cdk1+/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo.

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Section: Resultsmentioning

confidence: 99%

Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2

et al. 2008

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“…FUNG decreased diaph1 (diaphanous homolog 1) (via JUN target RHOA); decreased fasn (fatty acid synthase) and slc27a1 (solute carrier family 27 fatty acid transporter member 10) (via JUN target TNF) COMB decreased pias2 (miz1, Msx-interacting-zinc finger) (via JUN); increased rgs16 (regulator of G-protein signaling 16) (via JUN target TNF); and decreased dusp1 (dual specificity phosphatase 1) and znf385 (zinc finger protein 385) (via JUN target CDKN2A). Rgs16 is known to be decreased in response to G1/S activation in mouse liver, hence an increase could have a role in preventing cell progression [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, COMB down regulated: acta2 (actin, alpha 2) involved in smooth muscle contraction; arhgef7 (Rho guanine nucleotide exchange factor) and Sn (sialoadhesin) having roles in cell adhesion; and tubb2- and 3 (tubulins β 2 and -3), with roles in microtubule movement. Tubb 2 and 3 are known to be induced in response to G1/S activation in mouse liver [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…Plk1 and ntrk1 were decreased by COMB. Plk is known to be increased in response to G1/S activation in mouse liver (induced by partial partial hepatectomy), hence a decrease in plk1could decrease cell progression [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…Activating transcription factors (ATF) are basic region-leucine zipper (bZIP) proteins [ 46 ]. ATF5 can repress human cAMP-induced gene transcription [ 47 ] and may inhibit apoptosis and promote G1/S transitions [ 23 ]. COMB decreased atf5 would could increase apoptosis and inhibit G1/S progression.…”

Section: Resultsmentioning

confidence: 99%

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2006

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Introduction: Herein, we expand our previous work on the effects of long chain polyunsaturated fatty acids (LC-PUFA) on the murine hepatic transcriptome using novel statistical and bioinformatic approaches for evaluating microarray data. The analyses focuses on key differences in the transcriptomic response that will influence metabolism following consumption of FUNG (rich in 20:4n6), FISH (rich in 20:5n3, 22:5n3, and 22:6n3) and COMB, the combination of the two.Results: Using a variance-stabilized F-statistic, 371 probe sets (out of 13 K probe sets in the Affymetrix Mu11K chip set) were changed by dietary treatment (P < 0.001). Relative to other groups, COMB had unique affects on murine hepatic transcripts involved in cytoskeletal and carbohydrate metabolism; whereas FUNG affected amino acid metabolism via CTNB1 signaling. All three diets affected transcripts linked to apoptosis and cell proliferation, with evidence FISH may have increased apoptosis and decreased cell proliferation via various transcription factors, kinases, and phosphatases. The three diets affected lipid transport, lipoprotein metabolism, and bile acid metabolism through diverse pathways. Relative to other groups, FISH activated cyps that form hydroxylated fatty acids known to affect vascular tone and ion channel activity. FA synthesis and delta 9 desaturation were down regulated by COMB relative to other groups, implying that a FA mixture of 20:4n6, 20:5n3, and 22:6n3 is most effective at down regulating synthesis, via INS1, SREBP, PPAR alpha, and TNF signaling. Heme synthesis and the utilization of heme for hemoglobin production were likely affected by FUNG and FISH. Finally, relative to other groups, FISH increased numerous transcripts linked to combating oxidative such as peroxidases, an aldehyde dehydrogenase, and heat shock proteins, consistent with the major 22:5n3, 22:6n3) being more oxidizable than the major fatty acids in FUNG (20:4n6). Conclusion:Distinct transcriptomic, signaling cascades, and predicted affects on murine liver metabolism have been elucidated for 20:4n6-rich dietary oils, 22:6n3-rich oils, and a surprisingly distinct set of genes were affected by the combination of the two. Our results emphasize that the balance of dietary n6 and n3 LC-PUFA provided for infants and in nutritional and neutraceutical applications could have profoundly different affects on metabolism and cell signaling, beyond that previously recognized.

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T160‐phosphorylated CDK2 defines threshold for HGF‐dependent proliferation in primary hepatocytes

Mueller

Huard

Waldow

et al. 2015

Molecular Systems Biology

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Liver regeneration is a tightly controlled process mainly achieved by proliferation of usually quiescent hepatocytes. The specific molecular mechanisms ensuring cell division only in response to proliferative signals such as hepatocyte growth factor (HGF) are not fully understood. Here, we combined quantitative time-resolved analysis of primary mouse hepatocyte proliferation at the single cell and at the population level with mathematical modeling. We showed that numerous G1/S transition components are activated upon hepatocyte isolation whereas DNA replication only occurs upon additional HGF stimulation. In response to HGF, Cyclin:CDK complex formation was increased, p21 rather than p27 was regulated, and Rb expression was enhanced. Quantification of protein levels at the restriction point showed an excess of CDK2 over CDK4 and limiting amounts of the transcription factor E2F-1. Analysis with our mathematical model revealed that T160 phosphorylation of CDK2 correlated best with growth factor-dependent proliferation, which we validated experimentally on both the population and the single cell level. In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF.

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286 Gene expression profile at the G1/S boundary of liver regeneration after partial hepatectomy in mice

Cited by 3 publications

References 0 publications

Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2

Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2

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T160‐phosphorylated CDK2 defines threshold for HGF‐dependent proliferation in primary hepatocytes

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