Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation.

Franklin, David S.; Xiong, Yue

doi:10.1091/mbc.7.10.1587

Cited by 115 publications

(108 citation statements)

References 59 publications

(85 reference statements)

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“…Thus, it appears that one mixture of mitogen and hormonal agents utilized in the induction of differentiation activates two kinetically independent peaks of p21 protein expression, suggesting the possibility of two independent regulatory mechanisms based on the progression of proliferation versus differentiation. The decay in p21 in the presence of other CKIs during advanced stages of adipogenesis is consistent with other reports indicating a transient expression of p21 during myocyte differentiation in vitro (39) and during cardiac development in vivo (40). The association of p18, p21, and p27 with other proteins mediating both growth and differentiation is currently being investigated to ascribe specific functions of these CKIs during adipogenesis.…”

Section: Discussionsupporting

confidence: 88%

Role of PPARγ in Regulating a Cascade Expression of Cyclin-dependent Kinase Inhibitors, p18(INK4c) and p21(Waf1/Cip1), during Adipogenesis

Morrison

Farmer

1999

Journal of Biological Chemistry

285

223

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Molecular mechanisms coupling growth arrest and cell differentiation were examined during adipogenesis. Data are presented that document a cascade expression of members of two independent families of cyclin-dependent kinase inhibitors that define distinct states of growth arrest during 3T3-L1 preadipocyte differentiation. Exit from the cell cycle into a pre-differentiation state of post-mitotic growth arrest was characterized by significant increases in p21 and p27. During onset of irreversible growth arrest associated with terminal differentiation, the level of p21 declined with a concomitant, dramatic increase in p18 and a sustained level of p27. The expression of p18 and p21, regulated at the level of protein and mRNA accumulation, was directly coupled to differentiation. Stable cell lines were engineered to express adipogenic transcription factors to examine the active role of trans-acting elements in regulating these cell cycle inhibitors. Ectopic expression of peroxisome proliferator-activated receptor (PPAR) ␥ in non-precursor fibroblastic cell lines resulted in conversion to adipocytes and a coordinated increase in p18 and p21 mRNA and protein expression in a PPAR␥ ligandassociated manner. These data demonstrate a role for PPAR␥ in mediating the differentiation-dependent cascade expression of cyclin-dependent kinase inhibitors, thereby providing a molecular mechanism coupling growth arrest and adipocyte differentiation.

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Section: Discussionsupporting

confidence: 88%

Role of PPARγ in Regulating a Cascade Expression of Cyclin-dependent Kinase Inhibitors, p18(INK4c) and p21(Waf1/Cip1), during Adipogenesis

Morrison

Farmer

1999

Journal of Biological Chemistry

285

223

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“…2C). As described before in cell culture models, 19 complex formation of p18 with CDK4 and CDK6 could be shown, whereas no signal was detected on IP with CDK2 (Fig. 2C, lane 1).…”

Section: Expression Of P18supporting

confidence: 81%

“…Protein extracts were separated on a sodium dodecyl sulfide polyacrylamide gel and blotted as described previously. 29 Membranes were probed with anti-p18 (full length), 19 anti-proliferating cell nuclear antigen (PCNA; Santa Cruz Biotechnology), anti-cyclin D1, 30 and anti-CDK2, anti-p21 (#556431; BD Pharmingen, San Diego, CA), and anti-Kip1/p27 (#610241; BD Transduction Laboratories, Lexington, KY). As a secondary antibody, anti-rabbit immunoglobulin G (#711-035-152; Jackson Immuno Research Laboratories, Inc., West Grove, PA) or anti-mouse immunoglobulin G (#AQ 127P; Chemicon International, Temecula, CA) were used.…”

Section: Methodsmentioning

confidence: 99%

p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver

Luedde

Rodríguez²,

Tacke

et al. 2003

Hepatology

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p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p18(INK4c) for cell cycle progression in vivo is characterized poorly. Therefore, we studied the expression and physiologic relevance of p18 in quiescent and proliferating hepatocytes during liver regeneration. For our analysis we used single-(p18[INK4c], p27[KIP1], p21[CIP1/WAF1]), and double-mutant (p18/p21, p18/p27) mice. p18 expression was found in quiescent hepatocytes and a slight up-regulation was evident after partial hepatectomy (PH). p18 knockout animals showed normal cell cycle progression after PH. However, when p18/p21 and p18/ p27 double-mutant mice were used, differences in cell cycle progression were evident compared with wild-type (wt) and single knockout animals. In p18/p21 knockout animals, the G1 phase was shortened as evidenced by an earlier onset of cyclin D and proliferating cell nuclear antigen (PCNA) expression and cyclin-dependent kinase (CDK) activation after PH. In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2 -deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated. In conclusion, our results suggest that p18 is involved in cell cycle progression after PH. Additionally we provide evidence that timing and strength of DNA synthesis in hepatocytes after PH is regulated tightly through the collaboration of different cell cycle inhibitors. (HEPATOLOGY 2003;37:833-841.) T he most established experimental model for studying liver growth control in vivo is 70% partial hepatectomy (PH) in rodents, in which most of the remaining hepatocytes synchronously enter the cell cycle and liver mass is restored within 1 to 2 weeks. 1 The extracellular signals that trigger regeneration after PH recently have been studied extensively, 2-4 but less is known about the intracellular processes that regulate cell cycle control of hepatocytes under the influence of different extracellular conditions in vitro and especially in vivo.Progression through the different phases of the cell cycle is driven by protein complexes composed of a regulatory subunit, the cyclin, and a catalytic subunit, the cyclin-dependent kinase (CDK). In mammalian cells, CDK4 and CDK6 in combination with 3 D-type cyclins (D1, D2, and D3), and CDK2 in association with cyclin E, play key roles in regulating G1 phase progression. 5,6 Extracellular growth signals promote transcription of the cyclin D1 gene and assembly of cyclin D1-CDK4 complexes. 5-9 Active CDK4 and CDK2 complexes target and phosphorylate the retinoblastoma protein (Rb), leading to the activation of E2F proteins. [10][11][12] In addition to binding to cyclins, full activation of the CDKs requires phosphorylation by the CDK-activating kinase. 13 Another group of proteins have been identified that integrate growth inhibitory signals and inhibit CDK activation. The so-called CDK inhibitors (CDKIs) are classified into 2 ...

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“…13 P18 is highly expressed during myogenic differentiation, potentially mediating accompanying growth arrest by CDK4/CDK6 inhibition. 33 Thus, p18 appears to be a critical element in both differentiation and proliferation pathways and may serve as a marker for treatment response or as a target for new therapeutic approaches in MM.…”

Section: Discussionmentioning

confidence: 99%

Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis

et al. 2002

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Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.

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Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation.

Cited by 115 publications

References 59 publications

Role of PPARγ in Regulating a Cascade Expression of Cyclin-dependent Kinase Inhibitors, p18(INK4c) and p21(Waf1/Cip1), during Adipogenesis

Role of PPARγ in Regulating a Cascade Expression of Cyclin-dependent Kinase Inhibitors, p18(INK4c) and p21(Waf1/Cip1), during Adipogenesis

p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver

Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis

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