PMID- 10657902
OWN - NLM
STAT- MEDLINE
DCOM- 20000225
LR  - 20191024
IS  - 0899-1987 (Print)
IS  - 0899-1987 (Linking)
VI  - 27
IP  - 2
DP  - 2000 Feb
TI  - Tumor necrosis factor-alpha promotes human papillomavirus (HPV) E6/E7 RNA 
      expression and cyclin-dependent kinase activity in HPV-immortalized keratinocytes 
      by a ras-dependent pathway.
PG  - 97-109
AB  - Tumor necrosis factor-alpha (TNF-alpha) inhibits growth of normal cervical 
      keratinocytes but stimulates proliferation of human papillomavirus 
      (HPV)-immortalized and cervical carcinoma-derived cell lines when mitogens such 
      as epidermal growth factor (EGF) or serum are depleted. Current work identifies 
      the mechanism of growth stimulation. TNF-alpha promoted cell cycle progression by 
      increasing expression of HPV-16 E6/E7 RNAs and enhancing activity of 
      cyclin-dependent kinase (cdk)2 and cdc2 after 3 d. Increased kinase activity was 
      mediated by upregulation of cyclins A and B and decreases in cdk inhibitors 
      p21(waf) and p27(kip). TNF-alpha stimulated these changes in part by increasing 
      transcription and stabilization of RNA for amphiregulin, an EGF receptor ligand, 
      and amphiregulin directly increased HPV-16 E6/E7 and cyclin A RNAs. To define 
      which components of the EGF receptor signaling pathway were important, 
      HPV-immortalized cells were transfected with activated or dominant negative 
      mutants of Ha-ras, raf, or MAPKK. Expression of activated Ha-ras maintained 
      HPV-16 and cyclin gene expression and promoted rapid growth in the absence of 
      EGF. Furthermore, ras activation was necessary for TNF-alpha mitogenesis as 
      transfection with a dominant negative ras mutant (Asn-17) strongly inhibited 
      growth. Thus, activation of ras promotes expression of HPV-16 E6/E7 RNAs, induces 
      cyclins A and B, and mediates growth stimulation of immortal keratinocytes by 
      TNF-alpha. These studies define a pathway by which ras mutations, which occur in 
      a subset of cervical cancers, may contribute to pathogenesis. Mol. Carcinog. 
      27:97-109, 2000. Published by Wiley-Liss, Inc.
FAU - Gaiotti, D
AU  - Gaiotti D
AD  - Laboratory of Biology, National Cancer Institute, Bethesda, MD 20892-4255, USA.
FAU - Chung, J
AU  - Chung J
FAU - Iglesias, M
AU  - Iglesias M
FAU - Nees, M
AU  - Nees M
FAU - Baker, P D
AU  - Baker PD
FAU - Evans, C H
AU  - Evans CH
FAU - Woodworth, C D
AU  - Woodworth CD
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (E6 protein, Human papillomavirus type 16)
RN  - 0 (Oncogene Proteins, Viral)
RN  - 0 (Papillomavirus E7 Proteins)
RN  - 0 (RNA, Viral)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Repressor Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (oncogene protein E7, Human papillomavirus type 16)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Cell Cycle/genetics
MH  - Cell Line, Transformed
MH  - Cyclin-Dependent Kinases/*metabolism
MH  - Enzyme Activation/genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Keratinocytes/cytology/*enzymology/metabolism/virology
MH  - Oncogene Proteins, Viral/*genetics/metabolism
MH  - Papillomaviridae/*genetics/physiology
MH  - Papillomavirus E7 Proteins
MH  - RNA, Viral/*biosynthesis
MH  - Receptors, Tumor Necrosis Factor/biosynthesis/metabolism
MH  - *Repressor Proteins
MH  - Signal Transduction/*genetics
MH  - Tumor Necrosis Factor-alpha/*physiology
MH  - ras Proteins/*physiology
EDAT- 2000/02/05 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/05 09:00
PHST- 2000/02/05 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/05 09:00 [entrez]
AID - 10.1002/(SICI)1098-2744(200002)27:2<97::AID-MC5>3.0.CO;2-V [pii]
AID - 10.1002/(sici)1098-2744(200002)27:2<97::aid-mc5>3.0.co;2-v [doi]
PST - ppublish
SO  - Mol Carcinog. 2000 Feb;27(2):97-109. doi: 
      10.1002/(sici)1098-2744(200002)27:2<97::aid-mc5>3.0.co;2-v.