CDK-independent activities of D type cyclins

Bernards, René

doi:10.1016/s0304-419x(99)00024-4

Cited by 38 publications

(32 citation statements)

References 29 publications

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“…15 Signals initiated by estrogen, epidermal growth factor, and thyrotropin all converge on and activate Ccnd1/Cdk, 3,5,6 thereby stimulating proliferation of the target cell. 29 We found that maximum expression of Ccnd1 and cMyc in Ppar␣-null mice exhibited an approximately 1-day delay compared with wild-type mice. Similar to the reports of other investigators, 30 we observed no difference in mRNA levels of the primary inhibitor of G 1 /S transition in liver, p27 kip1 , between wild-type and Ppar␣-null mice.…”

Section: Discussionmentioning

confidence: 68%

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

et al. 2002

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Peroxisome proliferator chemicals, acting via the peroxisome proliferator-activated receptor-␣ (Ppar␣), are potent hepatic mitogens and carcinogens in mice and rats. To test whether Ppar␣ is required for hepatic growth in response to other stimuli, we studied liver regeneration and hepatic gene expression following partial hepatectomy (PH) of wild-type and Ppar␣-null mice. Ppar␣-null mice had a 12-to 24-hour delay in liver regeneration associated with a delayed onset and lower peak magnitude of hepatocellular DNA synthesis. Furthermore, these mice had a 24-hour lag in the hepatic expression of the G 1 /S checkpoint regulator genes Ccnd1 and cMyc and increased expression of the IL-1␤ cytokine gene. Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Ppar␣-null mice, after acute exposure to the potent Ppar␣ agonist Wy-14,643, indicating a role for Ppar␣ in regulating the expression of these genes. Expression of the fatty acid -hydroxylase gene Cyp4a14, a commonly used indicator gene for Ppar␣ activation, was strongly induced in wild-type mice after hepatectomy, suggesting that altered hepatocyte lipid processing may also contribute to the impaired regeneration in mice lacking the Ppar␣ gene. In conclusion, liver regeneration in Ppar␣-null mice is transiently impaired and is associated with altered expression of genes involved in cell cycle control, cytokine signaling, and fat metabolism. (HEPATOLOGY 2002;36:544-554.) P eroxisome proliferator (PP) xenobiotics are potent hepatic mitogens and carcinogens in mice and rats. 1 Increases in hepatocyte replication and tumor formation after PP exposure require activation of the peroxisome proliferator-activated receptor-␣ (Ppar␣). 2 Many transcriptional targets of Ppar␣ have been identified, but none have direct roles in regulating cell proliferation or apoptosis. One of the most effective models for studying hepatocellular proliferation is liver regeneration following hepatocellular loss because of partial hepatectomy (PH) or chemical damage. 3 In the original technique for PH described by Higgins and Anderson in 1931, 4 resection of 70% of the hepatic mass of a rat results in 95% of the remaining hepatocytes rapidly entering the cell cycle. DNA synthesis follows about 12 to 14 hours after resection and reaches a maximum activation at 24 hours. These events occur about 20 hours later in mice. The original mass of the liver is restored within 7 days, with most of the recovery occurring by 3 days. 4 The signals that stimulate and maintain this process are not entirely clear but include the transcriptional activation of several groups of genes in a distinct temporal order. 3,[5][6][7] First, hepatocytes must be primed, presumably by cytokines, to respond to various growth factors. After priming, transition from G 0 to G 1 phases of the cell cycle requires induction of immediate-early class genes, which begins at about 30 minutes post-PH and lasts for about 4 hours. Progression of hepatocytes in vivo through late G 1 phase requires gr...

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Section: Discussionmentioning

confidence: 68%

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

et al. 2002

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“…The segment of D-type cyclins required for its interaction with Dmp1 was mapped outside the 'cyclin box', which contains the residues predicted to contact Cdk4. Interestingly, the estrogen receptor and the steroid receptor co-activator bind with cyclin D1 outside the cyclin box, suggesting that the carboxylterminal half of cyclin D1 is important for its interaction with DNA-binding proteins (Bernards, 1999;Zwijsen et al, 1997). Coexpression of any of three D-type cyclins (D1, D2 or D3) with Dmp1 in mammalian cells canceled its ability to activate gene expression, which was independent of Cdks (Inoue and Sherr, 1998).…”

Section: Cip1mentioning

confidence: 99%

Dmp1 and tumor suppression

2007

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“…67 Cyclin D1 can form complexes with nuclear hormone receptors to modulate their transcriptional activity. [68][69][70][71] In addition, cyclin-cdk complexes can inhibit senescence or differentiation in a kinase-independent manner. 72 CDK inhibitors can also regulate cytoplasmic signaling pathways.…”

Section: A (Not So) Dirty Little Secret…mentioning

confidence: 99%