Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc.

Vlach, Jaromir; Hennecke, Silke; Alevizopoulos, Konstantinos; Conti, Daniela; Amati, Bruno

doi:10.1002/j.1460-2075.1996.tb01050.x

Cited by 322 publications

(368 citation statements)

References 71 publications

(116 reference statements)

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“…It has been reported that both G1 kinases, cdk4 and cdk2, are necessary to inactivate pRb (Lundberg and Weinberg, 1998). Furthermore, the fact that pRb was found in its faster-migrating, hypophosphorylated form, in the presence of active cdk4 is not surprising, as a similar result was reported (Vlach et al, 1996) in an experiment in which cdk2, but not cdk4, was inactivated in p27 kip1 -overexpressing Rat1 cells.…”

Section: Discussionsupporting

confidence: 57%

“…Since we have shown that [Lys 61 ]N-Ras can lead to cdk4 activation these cooperating alterations would help cdk2 activation. For instance, oncogenic myc expression, which cooperates with Ras to induce cell transformation, has been shown to be involved in p27 kip1 inactivation (Leone et al, 1997;Vlach et al, 1996). In cells with both oncogenic Ras and myc, activation of cdk2 could be achieved because the ratio of cyclin E/cdk2 complexes without p27 kip1 would increase.…”

Section: Discussionmentioning

confidence: 99%

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[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

et al. 2000

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The elements of the cell cycle regulatory machinery activated by the oncogenic form of Ras, [Lys 61 ]N-Ras, have been analysed in NIH3T3 cells. We demonstrate that [Lys 61 ]N-Ras expression is able to induce full cdk4 activation. As already reported, oncogenic Ras expression was su cient to induce cyclin D1 and p21 cip1 expression and their association with cdk4. Furthermore, serum-starved [Lys 61 ]N-Ras NIH3T3 cells showed nuclear accumulation of cyclin D1 and cdk4 not observed in serum-starved NIH3T3 cells. This accumulation of cdk4 into the cell nucleus observed in serum-starved [Lys 61 ]NRas NIH3T3 cells was inhibited by a microinjection of neutralizing anti-Ras antibodies. Thus, active [Lys 61 ]NRas was a su cient signal to induce nuclear accumulation of cyclin D1/cdk4, leading to its full activation. Transfection of [Lys 61 ]N-Ras NIH3T3 cells with an inactive form of MEK or their treatment with PD 98059, showed that nuclear translocation of cdk4 was MEK dependent. Interestingly, cells constitutively expressing [Lys 61 ]N-Ras did not inactivate pRb and did not proliferate in the absence of serum. This may be due to the fact that although association of cdk2 with cyclin E and the translocation of those complexes to the nucleus were achieved, [Lys 61 ]N-Ras expression was not su cient to induce cdk2 activation. The high levels of p27 kip1 that were found in cyclin E/cdk2 complexes may be responsible for the inability of oncogenic Ras to activate this kinase. In consequence, oncogenic alterations that lead to a decrease in p27 kip1 bound to cyclin E may cooperate with Ras to induce full cdk2 activation, pRb inactivation and thus cell proliferation. Oncogene (2000) 19, 690 ± 699.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

et al. 2000

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“…One possibility is that overexpression of D-or E-type cyclins leads to a higher associated kinase activity simply because more cyclin/CDK complexes are formed. However, higher cyclin/CDK kinase activity is not necessarily linked to higher amounts of the individual partner proteins because it depends on the activity of CAKs (CDK activating kinases) and the degree of phosphorylation (for a review see Draetta, 1997) and, in addition, cyclin/ CDK kinase complexes can be activated by releasing them from inactive high molecular weight complexes with inhibitors by still poorly de®ned biochemical steps (Steiner et al, 1995;Vlach et al, 1996). Thus, higher levels of a particular cyclin would not necessarily lead to the formation of more cyclin/CDK dimers with kinase activity.…”

Section: Discussionmentioning

confidence: 99%

“…The cyclin dependent kinase inhibitors (CKIs) p27 and p21 both inhibit D-and E-type cyclin/CDK activity and at least D-type cyclin/CDK complexes seem to depend on the activity of Myc to exert their function in G1 progression or for their activity as oncoproteins (Roussel et al, 1995;Haas et al, 1997). More recently, it was shown that overexpression of Myc but not cyclin D1 or cyclin E can overcome the p27 block in G1 (Vlach et al, 1996) also suggesting a regulatory function of Myc for G1 cyclin/ CDK complexes.…”

Section: Introductionmentioning

confidence: 99%

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Haas

Johannes²,

Geisen

et al. 1997

Oncogene

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We demonstrate in this paper that the G1 phase speci®c cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo ®broblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/ Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D-and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 speci®c cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The ®ndings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.

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“…The involvement of other factors in p27 sequestration cannot be excluded. For instance, c-myc indirectly induces sequestration of p27 in a form unable to bind cyclin E-cdk2, without induction of the ubiquitinmediated degradation of p27 (Vlach et al, 1996). In the dog thyroid, cAMP induces a biphasic increase of cmyc mRNA and protein (Pirson et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

et al. 1998

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Cell cycle proteins regulate the transitions from G1 to S and G2 to M phases. In higher eukaryotes, their function is controlled by intracellular cascades regulated by extracellular growth factors. We have studied in previously described transgenic mouse models for thyroid proliferative diseases the expression of the key proteins regulating the cell cycle by Western blotting and immunohistochemistry, and have correlated the observations with the known actions of the transgenes on the signal transduction cascades. In the adenosine A 2a receptor model, the cyclic AMP pathway, upstream of the Rb family cell division block, is constitutively activated. In the model expressing HPV 16 E7 protein, the Rb-like proteins are inhibited. Cyclin-dependent kinases cdk4, cdk2 and cdc2, and the associated cyclins D, E and A have been studied. Cyclin D3 appears as the major cyclin D subtype expressed in mouse thyroid epithelial cells in normal and transgenic mice. In the adenosine A 2a R model, all cell cycle proteins tested were accumulated. In the E7 model, all cell cycle proteins except for D-type cyclins and cdk4 were also accumulated. A similar pattern was observed in thyroids coexpressing both transgenes, suggesting a dominant e ect of E7 over the consequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21 cip1/waf1 and p27 kip1 were not downregulated in these proliferating thyroids which suggest other roles than the inhibition of the cell cycle progression.

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Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc.

Cited by 322 publications

References 71 publications

[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

[Lys61]N-Ras is able to induce full activation and nuclear accumulation of Cdk4 in NIH3T3 cells

Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity towards induction of cell death but requires functional Myc and CDK4

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

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