Decline and fall of the tumor suppressor

Hinkal, George; Donehower, Lawrence A.

doi:10.1073/pnas.0709330104

Cited by 6 publications

(4 citation statements)

References 16 publications

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“…Age-dependent increase in cancer incidence is largely attributed to an increased susceptibility to environmental carcinogens as age-related molecular changes occur over time in cells. In particular, the loss of tumor suppressive functions in cells plays a key role, which would result in the cells having accumulated genetic mutations over time, ultimately leading to aberrant cell growth and cancer development (Hinkal & Donehower, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of p53 during senescence in normal human keratinocytes

et al. 2015

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p53, the guardian of the genome, is a tumor suppressor protein and critical for the genomic integrity of the cells. Many studies have shown that intracellular level of p53 is enhanced during replicative senescence in normal fibroblasts, and the enhanced level of p53 is viewed as the cause of senescence. Here, we report that, unlike in normal fibroblasts, the level of intracellular p53 reduces during replicative senescence and oncogene-induced senescence (OIS) in normal human keratinocytes (NHKs). We found that the intracellular p53 level was also decreased in age-dependent manner in normal human epithelial tissues. Senescent NHKs exhibited an enhanced level of p16INK4A, induced G2 cell cycle arrest, and lowered the p53 expression and transactivation activity. We found that low level of p53 in senescent NHKs was due to reduced transcription of p53. The methylation status at the p53 promoter was not altered during senescence, but senescent NHKs exhibited notably lower level of acetylated histone 3 (H3) at the p53 promoter in comparison with rapidly proliferating cells. Moreover, p53 knockdown in rapidly proliferating NHKs resulted in the disruption of fidelity in repaired DNA. Taken together, our study demonstrates that p53 level is diminished during replicative senescence and OIS and that such diminution is associated with H3 deacetylation at the p53 promoter. The reduced intracellular p53 level in keratinocytes of the elderly could be a contributing factor for more frequent development of epithelial cancer in the elderly because of the loss of genomic integrity of cells.

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Section: Introductionmentioning

confidence: 99%

Regulation of p53 during senescence in normal human keratinocytes

et al. 2015

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“…(20,21) In accordance, in this study, most subjects with EGFR Exon 20 T790M were in the age of 45-65 years old. Advanced age may be associated with a reduced function of tumor-suppressor genes (22), potentially contributing to the occurrence of the EGFR Exon 20 T790M.…”

Section: Discussionmentioning

confidence: 99%

Osimertinib as a Potential Targeted Therapy for Non-Small Cell Lung Carcinoma (NSCLC) Patients with EGFR Exon 20 T790M

Zam,

Iskandar,

Tabri

et al. 2023

Indones Biomed J

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BACKGROUND: Emergence of drug resistance due to epidermal growth factor receptor (EGFR) Exon 20 T790M poses a challenge in the effective management of non-small cell lung carcinoma (NSCLC). Significant breakthrough in the management of NSCLC with a specific genetic alteration causes substantial condition improvement in patients whose cancer progressed after first-generation tyrosine kinase inhibitor treatment and who developed tumors with EGFR Exon 20 T790M mutation. The present study analyzed a cohort of NSCLC patients and investigated the incidence of the EGFR Exon 20 T790M status with Osimertinib therapy, along with its impact on survival rates.METHODS: This was a retrospective cohort study on 22 NSCLC subjects who were genetically examined for EGFR status from plasmic cell free total nucleic acid. Subjects with EGFR Exon 20 T790M mutation were treated with/without Osimertinib. Demographic and clinical data were descriptively summarized, and the differences of each variable and correlation between survival rate and EGFR Exon 20 T790M were analyzed.RESULTS: Subjects with (n=13) and without (n=9) EGFR Exon 20 T790M had survival rates of 10.77±2.45 and 4.78±1.48, respectively (p=0.000). Based on 1-year survival status of subjects with EGFR Exon 20 T790M, there were 3 Osimertinib-treated survivors and 2 Osimertinib-treated non-survivors. Eight subjects with EGFR Exon 20 T790M and without Osimertinib treatment did not survive (p=0.001).CONCLUSION: Since the treatment of Osimertinib demonstrated a noteworthy survival rate among NSCLC subjects with EGFR Exon 20 T790M, thus Osimertinib could be suggested as a potential targeted therapy for NSCLC subjects with EGFR Exon 20 T790M.KEYWORDS: non-small cell lung carcinoma, EGFR, Exon 20, T790M, osimertinib

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“…Cancer has been described as a disease of the elderly based on the observation that most tumors appear in the last quarter of life [ 43 ]. This is attributed to acquisition of mutations in genes encoding for oncogenes or tumor suppressors, 50% of which are associated with mutation of the p53 gene.…”

Section: Discussionmentioning

confidence: 99%

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

Guest

Ilić

Scrable

et al. 2015

Aging

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Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16–18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.

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Decline and fall of the tumor suppressor

Cited by 6 publications

References 16 publications

Regulation of p53 during senescence in normal human keratinocytes

Regulation of p53 during senescence in normal human keratinocytes

Osimertinib as a Potential Targeted Therapy for Non-Small Cell Lung Carcinoma (NSCLC) Patients with EGFR Exon 20 T790M

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

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