INT88412

Context Info Confidence 0.57 First Reported 2000 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 17 Total Number 17 Disease Relevance 8.49 Pain Relevance 1.66

endosome (CDK2) nucleoplasm (CDK2) cytoplasm (CDK2) cytosol (CDK2) mitosis (CDK2) nucleus (CDK2)

Anatomy Link Frequency SMCs 3 MCF-7 1 keratinocyte 1 stem cell 1 CDK2 (Homo sapiens)

Pain Link Frequency Relevance Heat withdrawal 20 99.28 cINOD 30 98.32 Inflammation 77 95.20 cocaine 584 94.40 palliative 2 72.56 adenocard 1 49.80 COX-2 inhibitor 52 32.24 antagonist 13 25.40 narcan 9 20.52 Opioid 13 11.68

Disease Link Frequency Relevance Heat Bullous Skin Disease 608 99.86 Acantholysis 130 99.12 Breast Cancer 61 98.96 Apoptosis 334 98.68 Reprotox - General 1 4 97.20 INFLAMMATION 92 95.20 Retinoblastoma 30 94.90 Hyperglycemia 53 94.56 Hypoxia 45 94.28 Cancer 411 91.48

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

All 3 COX inhibitors prevented CDK-2 activation.

Positive_regulation (activation) of CDK-2

1) Confidence 0.57 Published 2003 Journal Int. J. Cancer Section Abstract Doc Link 14566837 Disease Relevance 0.39 Pain Relevance 0.60

During G1 phase, the D-type cyclins (generally cyclin D1) are expressed in response to mitogenic signals, and by binding to CDK4 and CDK6, lead to activation of cyclin E/CDK2 and cyclin A/CDK2 in late G1 and S phase.

Positive_regulation (activation) of CDK2

2) Confidence 0.52 Published 2010 Journal BMC Cancer Section Body Doc Link PMC2914703 Disease Relevance 0.12 Pain Relevance 0

During G1 phase, the D-type cyclins (generally cyclin D1) are expressed in response to mitogenic signals, and by binding to CDK4 and CDK6, lead to activation of cyclin E/CDK2 and cyclin A/CDK2 in late G1 and S phase.

Positive_regulation (activation) of CDK2

3) Confidence 0.52 Published 2010 Journal BMC Cancer Section Body Doc Link PMC2914703 Disease Relevance 0.12 Pain Relevance 0

Studies on the mechanism of action indicate that BMP-7 treatment inhibits cyclin-dependent kinase 2 (cdk-2) that was stimulated during PDGF-BB-induced proliferation of SMCs and upregulates the expression of the inhibitory Smad, Smad6, which was shown to inhibit TGF-beta superfamily signaling.

Positive_regulation (stimulated) of cdk-2 in SMCs

4) Confidence 0.49 Published 2000 Journal J. Cell. Physiol. Section Abstract Doc Link 10825232 Disease Relevance 0 Pain Relevance 0.07

Studies on the mechanism of action indicate that BMP-7 treatment inhibits cyclin-dependent kinase 2 (cdk-2) that was stimulated during PDGF-BB-induced proliferation of SMCs and upregulates the expression of the inhibitory Smad, Smad6, which was shown to inhibit TGF-beta superfamily signaling.

Positive_regulation (stimulated) of cyclin-dependent kinase 2 in SMCs

5) Confidence 0.49 Published 2000 Journal J. Cell. Physiol. Section Abstract Doc Link 10825232 Disease Relevance 0 Pain Relevance 0.07

Activated CDK2 phosphorylates the downstream molecule pRb, which in turn promotes the expression of genes required for progression from G1 to S.

Positive_regulation (Activated) of CDK2

6) Confidence 0.44 Published 2008 Journal PLoS Medicine Section Body Doc Link PMC2504032 Disease Relevance 0.14 Pain Relevance 0.41

Cyclin A induces a conformational change in CDK2, and thereby permits activation of CDK2 through phosphorylation of Thr-160 catalyzed by CDK-activating kinase (CAK) [31].

Positive_regulation (activation) of CDK2

7) Confidence 0.44 Published 2008 Journal PLoS Medicine Section Body Doc Link PMC2504032 Disease Relevance 0.14 Pain Relevance 0.41

This reduction in Cdk2 kinase activity correlated with an increase in Cdk2/p21 complex formation in the OGF-exposed cells relative to control cultures at all time points.

Positive_regulation (increase) of Cdk2

8) Confidence 0.38 Published 2008 Journal Mol Cancer Section Body Doc Link PMC2253554 Disease Relevance 0.86 Pain Relevance 0

Retinoblastoma protein needs to be phosphorylated in order to release transcription factor E2F activating genes involved in the S phase-like PCNA (proliferating cell nuclear antigen) [82]. p53 is also important for the regulation of the G2/M transition, which requires activation of the cyclin B-cdk2 complex.

Positive_regulation (activation) of cdk2 associated with retinoblastoma

9) Confidence 0.20 Published 2010 Journal International Journal of Cell Biology Section Body Doc Link PMC2841246 Disease Relevance 0.31 Pain Relevance 0

was found up-regulated during vascular lesion formation and promoted post-confluent cell proliferation in vascular smooth muscle cells (VSMC) by increasing the cyclin A and CDK2 as well as decreasing p57kip2 [146].

Positive_regulation (increasing) of CDK2 in smooth muscle cells

10) Confidence 0.20 Published 2003 Journal Comp Hepatol Section Body Doc Link PMC151270 Disease Relevance 0.53 Pain Relevance 0

The biological plausibility of this excess energy hypothesis has been supported by a number of in vitro studies: Yamamoto et al. found that increasing glucose concentration in the culture media of MCF-7 breast cancer cells increased proliferation [30], mediated by an upregulation of cdk2 and cyclin D1 [31].

Positive_regulation (upregulation) of cdk2 in MCF-7 associated with breast cancer

11) Confidence 0.20 Published 2010 Journal Journal of Oncology Section Body Doc Link PMC2825545 Disease Relevance 0.93 Pain Relevance 0

We reported here a striking increase in CDK2 and cyclin E expression in HR animals.

Positive_regulation (increase) of CDK2

12) Confidence 0.20 Published 2006 Journal BMC Cancer Section Body Doc Link PMC1769509 Disease Relevance 0.78 Pain Relevance 0.05

Cyclin E and CDK2 protein levels are increased after carcinogen withdrawal

Positive_regulation (increased) of CDK2 associated with withdrawal

13) Confidence 0.18 Published 2006 Journal BMC Cancer Section Body Doc Link PMC1769509 Disease Relevance 0.19 Pain Relevance 0.05

As a result, the fully differentiated cells exhibited de-differentiated stem cell behaviors, including active growth with CDK1, CDK2, RUNX3, and the upregulation of several stemness genes, Rex1 along with the definitive downregulation of mature differentiation markers (Figure 1G).

Positive_regulation (upregulation) of CDK2 in stem cell

14) Confidence 0.14 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2817727 Disease Relevance 0.48 Pain Relevance 0

However, at present, it is unclear how continuing keratinocyte proliferation in consequence to increased c-Myc and cdk2 signalling contributes to acantholysis in PV.

Positive_regulation (increased) of cdk2 in keratinocyte associated with acantholysis and bullous skin disease

15) Confidence 0.13 Published 2008 Journal Histochem Cell Biol Section Body Doc Link PMC2413110 Disease Relevance 1.49 Pain Relevance 0

PV serum increased protein levels of cdk2 and PV serum-induced acantholysis in vivo was abolished by pharmacologic inhibition of cdk2.

Positive_regulation (increased) of cdk2 associated with acantholysis and bullous skin disease

16) Confidence 0.12 Published 2008 Journal Histochem Cell Biol Section Body Doc Link PMC2413110 Disease Relevance 1.52 Pain Relevance 0

Gefitinib has been shown to block EGFR downstream signal transduction pathways; this induces cell cycle arrest, which leads to accumulation of the cyclin-dependent kinase 2 inhibitor p27KIP1 and marked accumulation of hypophosphorylated Rb protein, which leads to G1 arrest [40].

Positive_regulation (accumulation) of cyclin-dependent kinase 2

17) Confidence 0.06 Published 2010 Journal Breast Cancer Res Section Body Doc Link PMC2972555 Disease Relevance 0.50 Pain Relevance 0

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