Cooperative transformation of 32D cells by the combined expression of IRS-1 and V-Ha-Ras View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2000-07-05

AUTHORS

Barbara Cristofanelli, Barbara Valentinis, Silvia Soddu, Maria Giulia Rizzo, Alessandra Marchetti, Gianluca Bossi, Anna Rita Morena, Michael Dews, Renato Baserga, Ada Sacchi

ABSTRACT

32D cells expressing v-Ha-Ras fail to show a transformed phenotype. Since Ras requires an active IGF-1R for transformation of fibroblasts, we asked whether expression of IRS-1 or Shc (two of the major substrates of the IGF-1R) could co-operate with oncogenic Ras in transforming 32D cells. We find that IRS-1, but not Shc, in combination with v-Ha-Ras generates a fully transformed phenotype in 32D cells. 32D cells expressing both IRS-1 and v-Ha-Ras (32D/IRS1/Ras) survive and proliferate in the absence of IL-3, do not undergo granulocytic differentiation in the presence of G-CSF and form tumors in nu/nu and syngeneic mice. In contrast, 32D cells expressing singly IRS-1 or v-Ha-Ras exhibit only a block in differentiation capacity. Over-expression of Shc proteins, by itself, promotes differentiation of 32D cells. Concomitant expression of IRS-1 and v-Ha-Ras synergistically phosphorylates ERK-1 and ERK-2 whereas a MEK inhibitor rapidly induces death of 32D/IRS1/Ras transformed cells. Furthermore, transformed 32D/IRS1/Ras cells display high levels of PI3-K activation and undergo rapid apoptosis when exposed to PI3-K inhibitors. The data indicate that: (1) a fully transformed phenotype in 32D cells is generated when a block in differentiation (v-Ha-Ras) is coupled with another differentiation block (IRS-1); (2) PI3-K and MAPK activity are required for the survival of transformed cells; (3) the signals generated by IRS-1 and oncogenic Ras converge on ERK and PI3-K resulting in high levels of activation. More... »

PAGES

3245-3255

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1203664

DOI

http://dx.doi.org/10.1038/sj.onc.1203664

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003529495

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/10918581


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36 schema:description Abstract32D cells expressing v-Ha-Ras fail to show a transformed phenotype. Since Ras requires an active IGF-1R for transformation of fibroblasts, we asked whether expression of IRS-1 or Shc (two of the major substrates of the IGF-1R) could co-operate with oncogenic Ras in transforming 32D cells. We find that IRS-1, but not Shc, in combination with v-Ha-Ras generates a fully transformed phenotype in 32D cells. 32D cells expressing both IRS-1 and v-Ha-Ras (32D/IRS1/Ras) survive and proliferate in the absence of IL-3, do not undergo granulocytic differentiation in the presence of G-CSF and form tumors in nu/nu and syngeneic mice. In contrast, 32D cells expressing singly IRS-1 or v-Ha-Ras exhibit only a block in differentiation capacity. Over-expression of Shc proteins, by itself, promotes differentiation of 32D cells. Concomitant expression of IRS-1 and v-Ha-Ras synergistically phosphorylates ERK-1 and ERK-2 whereas a MEK inhibitor rapidly induces death of 32D/IRS1/Ras transformed cells. Furthermore, transformed 32D/IRS1/Ras cells display high levels of PI3-K activation and undergo rapid apoptosis when exposed to PI3-K inhibitors. The data indicate that: (1) a fully transformed phenotype in 32D cells is generated when a block in differentiation (v-Ha-Ras) is coupled with another differentiation block (IRS-1); (2) PI3-K and MAPK activity are required for the survival of transformed cells; (3) the signals generated by IRS-1 and oncogenic Ras converge on ERK and PI3-K resulting in high levels of activation.
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44 CSF
45 ERK
46 ERK-2
47 IGF-1R
48 IL-3
49 IRS-1
50 IRS1/Ras
51 IRS1/Ras cells
52 MAPK activity
53 MEK inhibitors
54 Nu
55 PI3-K
56 PI3-K activation
57 PI3-K inhibitor
58 RA
59 RA cells
60 RA exhibit
61 Ras converge
62 Ras fail
63 Shc
64 Shc proteins
65 absence
66 absence of IL-3
67 activation
68 active IGF-1R
69 activity
70 apoptosis
71 block
72 capacity
73 cells
74 combination
75 combined expression
76 concomitant expression
77 contrast
78 converges
79 cooperative transformation
80 data
81 death
82 differentiation
83 differentiation block
84 differentiation capacity
85 exhibit
86 expression
87 expression of IRS-1
88 fail
89 fibroblasts
90 form tumors
91 granulocytic differentiation
92 high levels
93 inhibitors
94 levels
95 mice
96 nu/nu
97 oncogenic Ras
98 oncogenic Ras converge
99 phenotype
100 presence
101 protein
102 rapid apoptosis
103 signals
104 survival
105 syngeneic mice
106 transformation
107 transformation of fibroblasts
108 tumors
109 v-Ha
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