Dependence of Cyclin E-CDK2 Kinase Activity on Cell Anchorage

Fang, Fang; Orend, Gertraud; Watanabe, Nobumoto; Hunter, Tony; Ruoslahti, Erkki

doi:10.1126/science.271.5248.499

Cited by 342 publications

(284 citation statements)

References 44 publications

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“…Also, normal cells maintained in low serum (Firpo et al, 1994) or in suspension (Guadagno et al, 1993;Fang et al, 1996) do not express cyclin A and cannot progress into S-phase. Constitutive expression of cyclin A, but not cyclins D1 or E, allows NRK ®broblasts to proliferate in suspension (Guadagno et al, 1993), while induction of cyclin A expression can promote premature entry into S-phase of ®broblasts made quiescent by serum withdrawal (Resnitzky et al, Figure 2 Cells expressing wild-type E8 are capable of anchorageindependent growth in soft agar culture.…”

Section: Resultsmentioning

confidence: 99%

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

O'Brien

Campo

1998

Oncogene

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The E8 open reading frame of Bovine papillomavirus type 4 (BPV-4) encodes a small (42 amino acid) hydrophobic polypeptide localized to cellular membranes and capable of conferring an anchorage-independent (AI) growth phenotype on primary bovine cells co-transfected with BPV-4 E7 ORF and an activated ras gene. To further study the function of E8 independently of other viral gene products, we have expressed it in the murine ®broblast cell line, NIH3T3. Cells expressing E8 are capable of AI growth and escape growth arrest after serum withdrawal. E8 deregulates cyclin A expression, induces transactivation of the human cyclin A gene promoter and increases endogenous protein levels in cells maintained in short-term suspension culture and in lowserum (LS). Both these culture conditions promote downregulation of cyclin A in control cells. In LS growth conditions E8 permits sustained cyclin A-associated kinase activity but not cyclin E-cdk2 activity. Cyclin A-cdk2 activity and, in part, cyclin A gene expression are regulated by the cdk inhibitor p27 Kip1 . Expression of this cdk inhibitor is also de-regulated in E8 cells, with high levels being detected under all culture conditions tested. These data suggest that the ability of BPV-4 E8 to transform NIH3T3 cells is associated with upregulation of cyclin A-associated kinase activity and de-regulated expression of the cdk inhibitor p27 Kip1 and does not rely on down-regulation of p27 Kip1 expression. Analysis of E8 mutants indicate that the hydrophilic tail' of the molecule (residues 31 ± 42) is required for cell transformation, as assessed by anchorage-independent growth, while a form of E8 with expression restricted to the Endoplasmic Reticulum/cis-Golgi membranes by addition of a`KDEL' retention signal revealed that the sub-cellular localization is an important determinant of E8 biological activity.

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Section: Resultsmentioning

confidence: 99%

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

O'Brien

Campo

1998

Oncogene

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“…Integrins cooperate with RTKs to stimulate cyclin D1 expression and to suppress cyclin-dependent kinase inhibitor (cki) levels. In doing so, integrins support the cyclin Ecdk2 activity that drives S-phase entry [31,32]. The enhanced and sustained Erk activity in adherent cells (see above) explains in part the supportive role of integrins in cyclin D1 transcription [16,33].…”

Section: Regulation Of Proliferation Survival and Differentiation Bmentioning

confidence: 96%

Integrins in regulation of tissue development and function

Danen¹,

Sonnenberg²

2003

The Journal of Pathology

231

173

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Cell adhesion is indispensable for embryonic development and for proper tissue function. In metazoans, integrins are the major adhesion receptors that connect cells to components of the extracellular matrix. Integrins are implicated in assembly of extracellular matrices, cell adhesion and migration on extracellular matrices, and in vertebrates (in which the integrin family has expanded) they can also mediate cell-cell adhesion. Furthermore, integrinmediated adhesion can modulate many different signal transduction cascades and support cell survival, proliferation, and influence the expression of differentiation-related genes. In this review we briefly explain how integrins can affect so many different aspects of cell behavior and discuss evidence for roles of integrins in tissue development, function, and disease.

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“…The surprising temporary exit from the cell cycle following v-Src inactivation in the presence of serum growth factors may re¯ect another inhibitory environment. Cells transformed by v-Src display altered cell adhesions and cytoskeleton, possibly comparable in e ect to anchorage deprivation (Fang et al, 1996). While v-Src may allow cells in this state to continue cycling, in normal cells anchorage deprivation would be growth inhibitory.…”

Section: V-src Transformation and Cell Cycle Exitmentioning

confidence: 99%

Expression of the v-Src oncoprotein in fibroblasts disrupts normal regulation of the CDK inhibitor p27 and inhibits quiescence

1998

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To determine how an oncogenic tyrosine kinase disturbs cell cycle control we examined expression of cell cycle proteins and growth of ®broblasts reversibly transformed by a temperature sensitive mutant of v-Src (ts LA 29). ts LA 29 Rat-1 cells and normal Rat-1 cells had similar growth rates but the transformed cells traversed the G 1 phase of the cell cycle more rapidly and failed to exit cycle e ciently in response to serum starvation and cell con¯uence. Cyclin D1 and cyclin E levels were not elevated in growing ts LA 29 Rat-1 cells and the abbreviated G 1 was further accelerated by overexpression of cyclin E. A fall in cyclin E and cyclin A dependent kinase activities in Rat-1 cells in response to inhibitory growth conditions was abrogated in ts LA 29 Rat-1 cells and correlated with lack of p27 accumulation or cyclin A down regulation, the latter due to sustained cyclin A promoter activity. The expression of p27 mRNA was lower in ts LA 29 Rat-1 cells than Rat-1 cells and was elevated following v-Src inactivation concurrent with an increase in p27 promoter activity and temporary cell cycle exit. The suppression of mRNA or transcription is a novel way an oncoprotein can induce down regulation of p27 and contributes to the G 1 shortening and perturbed cell cycle regulation of the v-Src transformed cells.

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Dependence of Cyclin E-CDK2 Kinase Activity on Cell Anchorage

Cited by 342 publications

References 44 publications

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1

Integrins in regulation of tissue development and function

Expression of the v-Src oncoprotein in fibroblasts disrupts normal regulation of the CDK inhibitor p27 and inhibits quiescence

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