#p53

Cell Cycle Regulation

The G1/S transition is tightly regulated by:

Commitment to S phase involves transcriptional and posttranslational steps driven by Cyclin E-CDK2 activity pulse. During early G1, Cyclin D-CDK4/6 initiates partial Rb phosphorylation after mitogen induction, allowing modest E2F-dependent synthesis of Cyclin E. Rising Cyclin E binds CDK2, fully activating kinase normally restrained by inhibitors p21 and p27. Cyclin E-CDK2 hyperphosphorylates Rb at additional sites, liberating large pool of E2F1-3 which amplify expression of Cyclin A, Cdc6, MCM helicase components, dihydrofolate reductase and Pol alpha. Concurrently Cyclin E-CDK2 phosphorylate

Ref: Hinds & Weinberg, Cell Cycle Control by Cyclin E-CDK2, Curr Opin Cell Biol; Alberts et al., Chapter 17, G1/S Transition.

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Cell Cycle Regulation

What happens if p53 is mutated?

Functional p53 integrates stress signals, including DNA damage, oncogene activation, and hypoxia, to decide between cell cycle arrest, senescence, or apoptosis. Under normal conditions, wild-type p53 accumulates after ATM phosphorylates serine 15 and CHK2 phosphorylates serine 20, displacing E3 ubiquitin ligase MDM2 that normally targets p53 for proteasomal degradation. Transcriptional program includes CDKN1A encoding p21 inhibitor of CDK2-cyclin E and CDK4-cyclin D, causing Rb to remain hypophosphorylated and E2F-dependent S-phase entry genes repressed, imposing G1 arrest to allow repair. If

Ref: Vogelstein et al., Nature 2000, Surfing p53 Network; Levine & Oren, Nature Rev Cancer 2009, p53 Mutations.

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Cell Cycle Regulation

What is the role of p53 in the G1 checkpoint?

G1 progression toward S phase is driven by cyclin-dependent kinases CDK4/6-cyclin D and CDK2-cyclin E that phosphorylate retinoblastoma protein Rb, releasing transcription factor E2F to induce genes for DNA replication enzymes, nucleotide biosynthesis, and replication licensing factors such as Cdc6. DNA damage in G1 would risk copying lesions, necessitating arrest. Tumor suppressor p53 serves as guardian by acting as transcription factor stabilized upon ATM-CHK2 signaling after double-strand breaks. One of its principal targets is CDKN1A encoding p21CIP1/WAF1, a potent inhibitor of CDK2-cyclin

Ref: El-Deiry et al., Cell 1993, p21 as p53 Target; Bertoli et al., Nature Rev Mol Cell Biol 2013, G1-S Regulation.

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Cancer

Loss of p53 cooperates with Ras by

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

HPV E6 oncoprotein promotes cancer by

High-risk human papillomavirus oncoproteins E6 and E7 cooperate to drive cervical carcinogenesis. E7 binds and inactivates Rb, releasing E2F and promoting cell-cycle progression. E6 recruits the ubiquitin ligase E6AP to target p53 for degradation, thereby disabling the apoptotic and checkpoint responses that would otherwise eliminate the proliferating infected cell. The combined action removes both major tumor-suppressor barriers.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

p53 induces apoptosis mainly via activation of

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

Active p53 can induce cell cycle arrest by upregulating

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

DNA damage stabilizes p53 mainly by

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

p53 is normally kept at low levels due to

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

Loss of p53 function leads to

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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Cancer

p53 is often referred to as

The tumor-suppressor protein p53 is kept at low levels in unstressed cells by continuous MDM2-mediated ubiquitination and degradation. DNA damage or oncogenic stress leads to phosphorylation of p53 or induction of ARF, both of which block the p53–MDM2 interaction. Stabilized p53 then transcriptionally activates genes that induce cell-cycle arrest, DNA repair or apoptosis, thereby preventing propagation of damaged genomes.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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