Abstract
We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Δ26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Δ26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.
| Original language | English |
|---|---|
| Pages (from-to) | 5987-5997 |
| Number of pages | 11 |
| Journal | EMBO Journal |
| Volume | 17 |
| Issue number | 20 |
| DOIs | |
| Publication status | Published - Oct 15 1998 |
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Keywords
- CDK2
- E1A
- E2F
- p27(Kip1)
- Retinoblastoma
ASJC Scopus subject areas
- Genetics
- Cell Biology
Cite this
A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). / Alevizopoulos, Konstantinos; Catarin, Barbara; Vlach, Jaromir; Amati, Bruno.
In: EMBO Journal, Vol. 17, No. 20, 15.10.1998, p. 5987-5997.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1)
AU - Alevizopoulos, Konstantinos
AU - Catarin, Barbara
AU - Vlach, Jaromir
AU - Amati, Bruno
PY - 1998/10/15
Y1 - 1998/10/15
N2 - We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Δ26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Δ26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.
AB - We show here that the adenovirus E1A oncoprotein prevents growth arrest by the CDK2 inhibitor p27(Kip1) (p27) in rodent fibroblasts. However, E1A neither binds p27 nor prevents inhibition of CDK2 complexes in vivo. In contrast, the amount of free p27 available to inhibit cyclin E/CDK2 is increased in E1A-expressing cells, owing to reduced expression of cyclins D1 and D3. Moreover, E1A allows cell proliferation in the presence of supraphysiological p27 levels, while c-Myc, known to induce a cellular p27-inhibitory activity, is only effective against physiological p27 concentrations. E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2. Altogether, these findings imply that E1A can act downstream of p27 and CDK2. Retinoblastoma (pRb)-family proteins are known CDK substrates; as expected, association of E1A with these proteins (but not with p300/CBP) is required for E1A to prevent growth arrest by either p27 or the CDK4/6 inhibitor p16(INK4a). Bypassing CDK2 inhibition requires an additional function of E1A: the mutant E1A Δ26-35 does not overcome p27-induced arrest, while it binds pRb-family proteins, prevents p16-induced arrest, and alleviates pRb-mediated repression of E2F-1 transcriptional activity (although E1A Δ26-35 fails to restore expression of E2F-regulated genes in p27-arrested cells). We propose that besides the pRb family, E1A targets specific effector(s) of CDK2 in G1-S control.
KW - CDK2
KW - E1A
KW - E2F
KW - p27(Kip1)
KW - Retinoblastoma
UR - http://www.scopus.com/inward/record.url?scp=0032531871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032531871&partnerID=8YFLogxK
U2 - 10.1093/emboj/17.20.5987
DO - 10.1093/emboj/17.20.5987
M3 - Article
C2 - 9774342
AN - SCOPUS:0032531871
VL - 17
SP - 5987
EP - 5997
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 20
ER -