Tumor suppressor proteins as regulators of cell differentiation.
The products of the tumor suppressor genes are considered to function as specific inhibitors of tumor cell growth. In this communication, we present evidence to show that these proteins inhibit tumor cell proliferation by participating in the activation of tumor cell differentiation. The ML-1 human myeloblastic leukemia cells used in this study proliferate when treated with insulin-like growth factor I and transferrin but differentiate to monocytes when exposed to tumor necrosis factor alpha or transforming growth factor beta1, or to macrophage-like cells when treated with both these cytokines. Initiation of proliferation but not of differentiation was followed by a 20- to 25-fold increase in the nuclear level of the DNA polymerase-associated processivity factor PCNA and of the proliferation-specific transcription factor E2F1. In contrast, induction of differentiation but not of proliferation was followed by a 25- to 30-fold increase in the nuclear level of the tumor suppressor proteins p53 (wild type), pRb, and p130/Rb2 and of the p53-dependent cyclin kinase inhibitor p21/Cip1. p53 and p21/Cip1, respectively, inhibit the expression and activation of PCNA, whereas p130 and pRb, respectively, inhibit the expression and activation of E2F1. As a result, G1-S-associated DNA and mRNA synthesis is inhibited, growth uncoupled from differentiation, and maturation enabled to proceed. Where this function of the tumor suppressor proteins is impaired, the capacity for differentiation is lost, which leads to the sustained proliferation that is characteristic of the cancer cell.
Li
Z R
ZR
Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Hromchak
R
R
Mudipalli
A
A
Bloch
A
A
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology* / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016147:Genes, Tumor Suppressor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011506:Proteins; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis; D014168:Transferrin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016207:Cytokines; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050680:Transcription Factor DP1; D014157:Transcription Factors; D014168:Transferrin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I