Ki-ras and the Characteristics of Mouse Lung Tumors

Ramakrishna, Gayatri; Białkowska, Aneta; Perella, Christine M.; Birely, Lisa; Fornwald, Laura W.; Diwan, Bhalchandra A.; Shiao, Yih‐Horng; Anderson, Lucy M.

doi:10.1002/1098-2744(200007)28:3<156::aid-mc4>3.0.co;2-m

Cited by 14 publications

(4 citation statements)

References 40 publications

(35 reference statements)

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“…Here, additional total deletion of p27 in Cx32-KO lung (DKO) resulted in the complete loss of detectable MAPK-activated lung tumors (0%, Table 3, Figure 4h) in contrast to the increased activation observed in p27 þ / þ ,Cx32-KO mice (60%, Po0.005, Figure 4f). While activation of MAPK-related pathways is often correlated with tumor progression in mouse lung (Ramakrishna et al, 2002;Yao et al, 2003), here it cannot completely explain the increased MAPKactivation in p27 þ / þ ,Cx32-KO lung tumors as the sole bronchioloalveolar carcinoma (BAC) detected in a wild-type mouse was completely negative for MAPKactivation (Table 3). In addition, MAPK-activated bronchioloalveolar adenomas (BAA) increased in p27 þ / þ ,Cx32-KO and p27 þ /À,Cx32-KO mice.…”

Section: Dko Mice Exhibit Altered Mapk Activation Compared To Cx32-komentioning

confidence: 84%

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

et al. 2005

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Connexin32 knockout mice (Cx32-KO) exhibit increased chemical-and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27 KIP1 . To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (Po0.005) and Cx32-KO mice (P ¼ 0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (Po0.005) and DKO tumors (P ¼ 0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

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Section: Dko Mice Exhibit Altered Mapk Activation Compared To Cx32-komentioning

confidence: 84%

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

et al. 2005

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“…Activation of the pathway RAF1/MEK/ERK plays an important role in gene expression control during cell cycle, apoptosis, cell differentiation, and migration and is frequently associated with transformation of primary cells and tumor progression. In fact, recent studies suggest a possible role of Raf-1 in lung tumorigenesis (Yano et al, 1999;Ramakrishna et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

pRB2/p130 target genes in non-small lung cancer cells identified by microarray analysis

Russo

Claudio

et al. 2003

Oncogene

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The retinoblastoma gene family consisting of RB/p105, p107, and RB2/p130 cooperate to regulate cell-cycle progression through the G1 phase of the cell cycle. Previous data demonstrated an independent role for the reduction or loss of pRb2/p130 expression in the formation and/or progression of lung carcinoma. Rb2/ p130 is mutated in a human cell line of lung small cell carcinoma as well as in primary lung tumors. To identify potential pRb2/p130 target genes in an unbiased manner, we have utilized an adenovirus-mediated expression system of pRb2/p130 in a non-small lung cancer cell line to identify specific genes that are regulated by pRb2/p130. Using oligonucleotide arrays, a number of Rb2/p130 downregulated genes were identified and their regulation was confirmed by semiquantitative reverse transcriptionpolymerase chain reaction (RT-PCR) and Western blot analysis. As a result, 40 genes showed greater than 2.0-fold modification in their expression level after the RB2/ p130 viral transduction. In conclusion, coupling adenoviral overexpression with microarray and semiquantitative RT-PCR analyses proved to be a versatile strategy for identifying pRb2/p130 target genes and for better understanding the expression profiles of these genes. Our results may also contribute to identifying novel therapeutic biomarkers in lung carcinoma.

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“…(1,2,5,6) and C57BL mice (3,4,7,8) treated (2,4,6,8) and untreated with 3 MC (1, 3, 5, 7). (1,2,5,6) and C57BL mice (3,4,7,8) treated (2,4,6,8) and untreated with 3 MC (1, 3, 5, 7).…”

Section: Resultsmentioning

confidence: 99%

“…a) Competitive analysis: 1) free probe; 2) binding to proteins of the extract from lung cell nuclei in the absence of competitive oligonucleotides;3 5) in the presence of 25 , 50 , and 100 fold excess oligonucleotide corresponding to the binding site for NF Y; 6, 7) in the presence of 50 and 100 fold excess oligonucleotide corresponding to the binding site for GATA;8,9) in the presence of 100 fold excess oligonucleotides corresponding to the binding sites for LKLF and Ets. a) Competitive analysis: 1) free probe; 2) binding to proteins of the extract from lung cell nuclei in the absence of competitive oligonucleotides;3 5) in the presence of 25 , 50 , and 100 fold excess oligonucleotide corresponding to the binding site for NF Y; 6, 7) in the presence of 50 and 100 fold excess oligonucleotide corresponding to the binding site for GATA;8,9) in the presence of 100 fold excess oligonucleotides corresponding to the binding sites for LKLF and Ets.…”

mentioning

confidence: 99%

Codon 12 Region of Mouse K-ras Gene Is the Site for in vitro Binding of Transcription Factors GATA-6 and NF-Y

Gorshkova

Каледин

Кобзев

et al. 2005

Biochemistry (Moscow)

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Codon 12 of the K-ras gene is a generally recognized example of a mutational hot spot. By the approach of gel retardation and specific antibodies, a double-stranded oligonucleotide corresponding to the codon 12 region of the mouse K-ras gene (from 20 to 50 bp with respect to the exon 1 start) was found to be a site for cooperative binding of the transcription factors GATA-6 and NF-Y. GATA-6 and NF-Y were selectively activated with lung carcinogens 3-methylcholanthrene and nitrosoethylurea in mice of strains susceptible to lung tumorigenesis but not in animals of resistant strains. The interaction of GATA-6 and NF-Y with the codon 12 region of the K-ras gene is suggested to be involved in the mechanism of lung carcinogenesis.

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Ki-ras and the Characteristics of Mouse Lung Tumors

Cited by 14 publications

References 40 publications

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

pRB2/p130 target genes in non-small lung cancer cells identified by microarray analysis

Codon 12 Region of Mouse K-ras Gene Is the Site for in vitro Binding of Transcription Factors GATA-6 and NF-Y

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