Immortalization of primary human prostate epithelial cells by c-Myc.
A significant percentage of prostate tumors have amplifications of the c-Myc gene, but the precise role of c-Myc in prostate cancer is not fully understood. Immortalization of human epithelial cells involves both inactivation of the Rb/p16INK4a pathway and telomere maintenance, and it has been recapitulated in culture by expression of the catalytic subunit of telomerase, hTERT, in combination with viral oncoproteins. Here, we show the immortalization of human prostate epithelial cells (HPrEC) by a single genetic event, the expression of the c-Myc oncogene. Myc stabilizes telomere length in HPrEC through up-regulation of hTERT expression and overrides the accumulation of cell cycle inhibitory proteins, such as p16INK4a. Overall, HPrECs expressing c-Myc retain many characteristics of normal cells, such as the induction of a senescence-like growth arrest in response to oncogenic Ras, an intact p53 response, and an absence of gross karyotypic abnormalities. However, HPrECs expressing c-Myc lack a Rb/p16INK4a checkpoint and can be transformed without the need for additional genetic lesions in that pathway. These results give a partial explanation for the physiologic role of c-Myc overexpression in prostate cancer.
Gil
Jesús
J
Molecular Oncology Laboratory, Cancer Research UK, London Research Institute, United Kingdom. jesus.gil@cancer.org.uk
Kerai
Preeti
P
Lleonart
Matilde
M
Bernard
David
D
Cigudosa
Juan Cruz
JC
Peters
Gordon
G
Carnero
Amancio
A
Beach
David
D
D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D005784:Gene Amplification; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D011467:Prostate / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019098:Telomerase / Q000378:metabolism
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase