Bcl-xL gain of function and p19 ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms.
Overexpression of Bcl-xL, loss of p19 ARF, and loss of p53 all accelerate Myc oncogenesis. All three lesions are implicated in suppressing Myc-induced apoptosis, suggesting that this is a common mechanism by which they synergize with Myc. However, using an acutely switchable model of Myc-induced tumorigenesis, we demonstrate that each lesion cooperates with Myc in vivo by a distinct mechanism. While Bcl-xL blocks Myc-induced apoptosis, inactivation of p19 ARF enhances it. However, this increase in apoptosis is matched by increased Myc-induced proliferation. p53 inactivation shares features of both lesions, partially suppressing apoptosis while augmenting proliferation. Bcl-xL and p19 ARF loss together synergize to further accelerate Myc oncogenesis. Thus, differing lesions cooperate oncogenically with Myc by discrete mechanisms that can themselves synergize with each other.
Finch
Andrew
A
Cancer Research Institute and Department of Cellular and Molecular Pharmacology, UCSF Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, California 94143, USA.
Prescott
Julia
J
Shchors
Ksenya
K
Hunt
Abigail
A
Soucek
Laura
L
Dansen
Tobias B
TB
Swigart
Lamorna Brown
LB
Evan
Gerard I
GI
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016259:Genes, myc / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology*
C494812:Bcl2l1 protein, mouse; C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein