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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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p53 regulated senescence mechanism and role of its modulators in age-related disorders

Girija Pawge1, Gopal L Khatik1

  • 1Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research- Raebareli, New Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226301, India.

Biochemical Pharmacology
|June 12, 2021
PubMed

Insights

Cellular senescence drives aging and age-related diseases. Targeting p53 upstream regulators with senolytic therapies offers a promising strategy to prevent these conditions in the elderly.

Area of Science:

  • Gerontology and Cellular Biology
  • Molecular Biology and Genetics
  • Pharmacology and Drug Discovery

Background:

  • Aging is linked to multiple co-morbidities, necessitating broad-spectrum drugs for the geriatric population to avoid adverse effects from polypharmacy.
  • Cellular senescence, a key aging mechanism, involves the tumor suppressor protein p53, which regulates DNA damage responses, apoptosis, and the senescence-associated secretory phenotype (SASP).

Purpose of the Study:

  • To review the role of p53 in DNA damage-induced senescence.
  • To explore upstream regulators of p53, including FOXO4, MDM2, MDM4, and USP7.
  • To discuss senolytic therapies targeting p53 pathways and potential small molecule senotherapeutics.

Main Methods:

  • Literature review focusing on p53's role in senescence.
  • Analysis of upstream regulatory proteins and pathways of p53.
  • Identification and discussion of small molecules targeting p53 upstream regulators.

Main Results:

  • p53 is crucial in forming DNA damage-induced senescence (DNA-SCARS).
  • Upstream targets like FOXO4, MDM2, MDM4, and USP7 modulate p53 availability for apoptosis and SASP regulation.
  • Small molecules targeting these upstream regulators show potential for senotherapeutic development.

Conclusions:

  • Modulating p53 upstream targets via senolytic therapies is a viable strategy for preventing age-related disorders.
  • Medicinal chemistry approaches can optimize small molecules for effective senotherapeutics.
  • Targeting p53 pathways offers a novel approach to combat age-related diseases.
Keywords:
Age-related disorderNeurodegenerationSenescenceSenolytic drugsp53 regulation

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