Regulation of p27(KIP1) by the PI3K/PKB pathway and its role in cell cycle progression in human cancer
Bibliographic record
Abstract
TGF-beta induces G1 phase cell cycle arrest in normal epithelial cells. Most tumor cells are resistant to TGF-beta, which is associated with Ras activation. The role played by a Ras effector, the PI3K/PKB pathway, in the cell cycle was investigated in this thesis. The cdk inhibitor p27KIP1 binds to and inhibits cyclin E-cdk2 in response to TGF-beta. This response is defective in TGF-beta resistant cells. We showed increased PKB activation and cytoplasmic mislocalization of p27 in TGF-beta resistant lines. Transfection of constitutively active PKB conferred TGF-beta resistance. PKB phosphorylates p27 on threonine 157 (T157) and impairs its nuclear import. PI3K/PKB inhibition abolished p27T157 phosphorylation and restored TGF-beta-induced cyclin E-cdk2 inhibition by p27 and G1 arrest. Cytoplasmic p27 mislocalization was associated with PKB activation and with poor patient prognosis in 40% of primary breast cancers. This study has brought to light a novel mechanism whereby PKB impairs p27 function during oncogenesis. In summary, constitutive PKB-dependent phosphorylation of p27 leads to cytoplasmic mislocalization of p27, whereas the assembly function of p27 toward cyclin D1-cdk4 is activated through both PKB-dependent and PKB-independent sequential changes in p27 phosphorylation. PKB over-activation leads to p27 sequestration in cytoplasm or in cyclin D-cdk complexes and may contribute to loss of the cyclin E-cdk2 inhibitory function of p27 and TGF-beta resistance.p27KIP1 also acts as an assembly factor for cyclin D-cdk4 or cdk6 in a mitogen-dependent manner. We showed that following growth factor stimulation, PKB activation precedes cyclin D1-cdk4-p27KIP1 assembly in early G1. Inhibition of the PI3K/PKB pathway resulted in loss of cyclin D1 from p27 complexes and a shift of p27 into cyclin E-cdk2. PKB-dependent p27 phosphorylation increased the ability of p27 to assemble cyclin D1-cdk4. Cyclin D1-bound p27 is discretely phosphorylated at multisites including N-terminal S10 and C-terminal S178/T187 and T198, differing significantly from cdk2-bound p27.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".