Loss of p16: A Bouncer of the Immunological Surveillance?

Leon, Kelly E.; Tangudu, Naveen K.; Aird, Katherine M.; Buj, Raquel

doi:10.3390/life11040309

Cited by 14 publications

(13 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of different open reading frames on the locus generates in both species’ alternative proteins (p14p14ARF in humans and p19ARF in mice). In comparison to p16INK4A, they differ in the first exon while they share the second exon, resulting in the translation of different reading frames [ 44 , 45 ] (reviewed in [ 46 ]). The p21 gene ( CDKN1A ) is completely independent and localized on chromosomes 6 and 17 in humans and mice, respectively.…”

Section: P16ink4a P14arf/p19arf and P21—basic Molecular Mechanismsmentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

View full text Add to dashboard Cite

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

show abstract

Section: P16ink4a P14arf/p19arf and P21—basic Molecular Mechanismsmentioning

confidence: 99%

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Wagner

2022

Cells

View full text Add to dashboard Cite

show abstract

“…The importance of these and other SASP factors has been verified in multiple biological contexts. 56–63 Interestingly, the control of the SASP itself by RELA/p65, which we detected in two sequencing datasets of aging women, has recently been experimentally verified in U2OS osteosarcoma cells. 64…”

Section: Discussionmentioning

confidence: 56%

“…The importance of these and other SASP factors has been verified in multiple biological contexts. [56][57][58][59][60][61][62][63] Interestingly, the control of the SASP itself by RELA/p65, which we detected in two sequencing datasets of aging women, has recently been experimentally verified in U2OS osteosarcoma cells. 64 Transcriptome-wide state-of-the-art technologies such as scRNA-seq will help shape our understanding of not just aging, but also therapeutics that potentially target fundamental mechanisms of aging, such as senolytics.…”

Section: Discussionmentioning

confidence: 59%

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

View full text Add to dashboard Cite

Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

show abstract

“…p16inka (p16) is a cyclin-dependent kinase inhibitor involved in the normal cycle of somatic cells and acts as a tumor suppressor [ 44 ]. p16 overexpression is associated with keeping the retinoblastoma protein (Rbp) in an unphosphorylated state which deaccelerates cell cycle progression from G1 to S phase [ 85 , 86 ]. Viral oncogenes E6 and E7 are known to be drivers of proliferation, promoting and maintaining the malignant growth of cervical cells in the process of high-risk HPV-linked carcinogenesis [ 13 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of p16/Ki-67 Immunostaining, hTERC Amplification and Fibronectin in Predicting Cervical Cancer Progression: A Systematic Review

Voidăzan

Dianzani

Husariu

et al. 2022

Biology

View full text Add to dashboard Cite

Human papillomaviruses (HPVs) are common sexually transmitted infectious agents responsible for several anogenital and head and neck cancers. Cervical cancer (CC) is the fourth leading cause of death in women with cancer. The progression of a persistent HPV infection to cancer takes 15–20 years and can be preventable through screening. Cervical cytology (Pap smear) is the standard screening test for CC and precancerous lesions. For ASC-US and ASC-H lesions, a combination of Pap smear and HR-HPV analysis is recommended as a triage step before colposcopy. However, these tests cannot predict progression to CC. For this purpose, we summarized current scientific data on the role of p16/Ki-67 immunohistostaining, telomerase and fibronectin in predicting progression to CC. p16 and p16/Ki-67 dual staining (DS) were more specific than HR-HPV DNA testing for the detection of CIN2+/CIN3+ in women with ASC-US and LSIL. Similarly, hTERC FISH analysis significantly improved the specificity and positive predictive value of HPV DNA testing in differentiating CIN2+ from CIN2 cytological samples. In conclusion, p16 IHC, p16/Ki-67 DS and hTERC FISH amplification are all valid adjunctive biomarkers which significantly increase the sensitivity and specificity of cervical dysplasia diagnosis, especially when combined with HPV DNA testing. However, considering the global socioeconomic background, we can postulate that p16 and p16/ Ki-67 IHC can be used as a next step after positive cytology for ASC-US or LSIL specimens in low-income countries, instead of HPV DNA testing. Alternatively, if HPV DNA testing is covered by insurance, p16 or p16/Ki-67 DS and HPV DNA co-testing can be performed. In middle- and high-income countries, hTERC amplification can be performed as an adjunctive test to HPV DNA testing in women with ASC-US and LSIL.

show abstract

Loss of p16: A Bouncer of the Immunological Surveillance?

Cited by 14 publications

References 111 publications

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

The Role of p16/Ki-67 Immunostaining, hTERC Amplification and Fibronectin in Predicting Cervical Cancer Progression: A Systematic Review

Contact Info

Product

Resources

About