Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex

Autor: Toshiyuki Kobayashi, Okio Hino
Rok vydání: 2017
Předmět:
Pluripotent Stem Cells
0301 basic medicine
two‐hit hypothesis
congenital
hereditary
and neonatal diseases and abnormalities
Cancer Research
Review Article
tuberous sclerosis complex
mTORC1
Mechanistic Target of Rapamycin Complex 1
Gene mutation
Biology
Eker rat
medicine.disease_cause
Tuberous Sclerosis Complex 1 Protein
retinoblastoma
03 medical and health sciences
Tuberous sclerosis
Germline mutation
Tuberous Sclerosis
Tuberous Sclerosis Complex 2 Protein
medicine
Animals
Humans
Genes
Tumor Suppressor
tumor suppressor gene
Induced pluripotent stem cell
Models
Genetic
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins
General Medicine
medicine.disease
Rats
nervous system diseases
Disease Models
Animal
Drosophila melanogaster
030104 developmental biology
medicine.anatomical_structure
Oncology
Organ Specificity
Multiprotein Complexes
Cancer research
TSC1
TSC2
Carcinogenesis
Signal Transduction
Zdroj: Cancer Science
ISSN: 1347-9032
DOI: 10.1111/cas.13116
Popis: On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two‐hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor‐predisposing syndromes. To understand the molecular mechanism of two‐hit‐initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor‐predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1‐independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.
Databáze: OpenAIRE
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