Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Müller, Daniel; Bouchard, Caroline; Rudolph, Bettina; Steiner, Philipp; Stuckmann, Ingo; Saffrich, Rainer; Ansorge, Wilhelm; Huttner, Wieland B.; Eilers, Martin

doi:10.1038/sj.onc.1201440

Cited by 153 publications

(142 citation statements)

References 44 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…For example, a Myc-regulated heat-labile inhibitor of p21 has been described (20). By an apparently similar mechanism, in cells which express abundant p27 but little p21, Myc induction inhibits the ability of p27 to bind cyclin E-Cdk2, most likely by causing the p27 to be sequestered (34,41,62). While cyclin D-Cdk4 or cyclin D-Cdk6 complexes provide an attractive possibility for the sequestration of p27 or p21, increased association between these proteins and p27 was not observed following c-Myc induction (62).…”

Section: Discussionmentioning

confidence: 92%

“…Similarly, data from this laboratory suggest that following c-Myc induction in human breast cancer cells, p21 and p27 are not sequestered by cyclin D-Cdk4 (43). Recent data suggest that the sequestered p27 is targeted for degradation, raising the possibility that the sequestering proteins are involved in the degradation process (34). It is possible that the decrease in c-myc expression following progestin treatment results in decreased expression of p21-and p27-sequestering molecules, contributing to increased availability of p21 and p27 for cyclin-CDK binding.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins

Musgrove

Swarbrick

Lee

et al. 1998

Molecular and Cellular Biology

121

118

View full text Add to dashboard Cite

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. In breast cancer cells the predominant effect of synthetic progestins is long-term growth inhibition and arrest in G 1 phase. Progestin-mediated growth arrest of T-47D breast cancer cells was preceded by inhibition of cyclin D1-Cdk4, cyclin D3-Cdk4, and cyclin E-Cdk2 kinase activities in vitro and reduced phosphorylation of pRB and p107. This was accompanied by decreases in the expression of cyclins D1, D3, and E, decreased abundance of cyclin D1-and cyclin D3-Cdk4 complexes, increased association of the cyclin-dependent kinase (CDK) inhibitor p27 with the remaining Cdk4 complexes, and changes in the molecular masses and compositions of cyclin E complexes. In control cells cyclin E eluted from Superdex 200 as two peaks of ϳ120 and ϳ200 kDa, with the 120-kDa peak displaying greater cyclin E-associated kinase activity. Following progestin treatment, almost all of the cyclin E was in the 200-kDa, low-activity form, which was associated with the CDK inhibitors p21 and p27; this change preceded the inhibition of cell cycle progression. These data suggest preferential formation of this higher-molecular-weight, CDK inhibitorbound form and a reduced number of cyclin E-Cdk2 complexes as mechanisms for the decreased cyclin E-associated kinase activity following progestin treatment. Ectopic expression of cyclin D1 in progestininhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression. Thus, decreased cyclin expression and consequent increased CDK inhibitor association are likely to mediate the decreases in CDK activity accompanying progestin-mediated growth inhibition.Steroid hormones regulate cellular proliferation and differentiation by cell cycle phase-specific actions (40). Estrogen, acting in concert with other hormones and growth factors, appears to be the main drive to proliferation in the female reproductive tract and mammary gland. In contrast with the proliferative effects of estrogen, progesterone acts as the differentiating female sex steroid. In this role it can either stimulate or inhibit proliferation in a cell type-and tissue-specific manner (5). For example, the primary function of progesterone in the uterus is to facilitate implantation, and in this organ progesterone acts synergistically with estrogen to stimulate proliferation of stromal cells but inhibits estrogen-induced mitosis in the epithelium. In the mammary gland progesterone stimulates proliferation and development of alveoli, a requirement for subsequent lactation. In breast cancer cells, a widely used model for studies of the effects of steroids on cell proliferation, treatment with synthetic progestins results in a biphasic change in the rate of cell cycle progression, consisting of an initial transient acceleration through G 1 phase and a subsequent increase in the S phase fraction, followed by cell cycle arrest and growth...

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins

Musgrove

Swarbrick

Lee

et al. 1998

Molecular and Cellular Biology

121

118

View full text Add to dashboard Cite

show abstract

“…Indeed, regulation of p27 Kip1 protein degradation seems to be the most important mechanism by which this important CKI is regulated. It is known that p27 Kip1 degradation occurs via ubiquitination ( [92]; reviewed in [93]), because p27 Kip1 is phosphorylated on Thr 187 by Cdk2/cyclin E and this phosphorylated form is then targeted for ubiquitination and degradation [94][95][96][97]. Pagano and coworkers [98] demonstrated that ubiquitination of p27 Kip1 requires prior phosphorylation of p27 Kip1 on Thr187 as well as trimeric complex formation among p27 Kip1 , Cdk2 and cyclin A or E. As expected, proteasome inhibitors lead to p27 Kip1 accumulation [99].…”

Section: Cdc25a Phosphatasementioning

confidence: 99%

“…For example, induction of c-MycER fusion protein by 4-OH tamoxifen in Rat1 fibroblasts leads to Cdk2/cyclin E activation. This is a result of: i) inhibition of p27 Kip1 binding to the Cdk2/cyclin E complexes [104], ii) p27 Kip1 release from the Cdk2/cyclin E complexes [97], and iii) p27 Kip1 degradation [105]. Furthermore, retroviral expression of p27 Kip1 induces G1 arrest in parental Rat1 cells, but not in Rat1 cells that ectopically express c-Myc [106].…”

Section: Cdc25a Phosphatasementioning

confidence: 99%

Regulation of the G1 phase of the mammalian cell cycle

2000

View full text Add to dashboard Cite

In any multi-cellular organism, the balance between cell division and cell death maintains a constant cell number. Both cell division cycle and cell death are highly regulated events. Whether the cell will proceed through the cycle or not, depends upon whether the conditions required at the checkpoints during the cycle are fulfilled. In higher eucaryotic cells, such as mammalian cells, signals that arrest the cycle usually act at a G1 checkpoint. Cells that pass this restriction point are committed to complete the cycle. Regulation of the G1 phase of the cell cycle is extremely complex and involves many different families of proteins such as retinoblastoma family, cyclin dependent kinases, cyclins, and cyclin kinase inhibitors.Key words: Cell cycle, cyclin dependent kinase, cyclin, cyclin kinase inhibitor. Retinoblastoma family of proteinsThe retinoblastoma family consists of three members: pRb, p107, and p130, that are all important in the cell cycle regulation. Studies from knockout mice showed that pRb null mutation is embryonically lethal, while p107 or p130 knockout mice have no known * Corresponding author.Tel: (301) 517-0355; Fax: (301) 517-0344; E-mail: scottd@usa.redcross.org Abbreviations used in this paper: pRb,retinoblastoma protein; CDK, cyclin dependent kinase; CKI, cyclin kinase inhibitor; IgM, immunoglobulin M; BCR, B cell receptor; BHFR, dihydrofolate reductase; TGF-β, transforming growyh factorβ.

show abstract

“…Whereas P27 needs to be transported into the nucleus to exert its effect on the cell cycle (30), degradation of p27 by a ubiquitin-dependent pathway requires cytoplasmic localization of p27 (31,32). Thus, the next question that we addressed was the role of Rac1 on the Ang II-induced nuclear translocation of p27.…”

Section: Modulatory Effect Of Smv On Ang Ii-induced Rac1 Activationmentioning

confidence: 99%

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Zeng¹,

Xu²,

Chew

et al. 2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 M) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 M) or geranylgeranyl pyrophosphate (5 M) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H 2 O 2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H 2 O 2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.

show abstract

Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from cyclin E/cdk2 complexes

Cited by 153 publications

References 44 publications

Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins

Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins

Regulation of the G1 phase of the mammalian cell cycle

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Contact Info

Product

Resources

About