Table of Contents
Is p14arf a tumor suppressor?
P14ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14ARF functions can be played through interactions with several proteins.
What kind of protein is p14ARF?
p14ARF (p19Arf in mice) is a 14kDa (19 kDa) protein predominantly localized in the nucleolus. It blocks the cell cycle in both G1 and G2 phases and inhibits the growth of incipient cancer cells by indirectly activating p53. It also inhibits ribosomal RNA processing and interacts with topoisomerase I.
What is the link between p14ARF and p53?
Here we show that E2F-1 directly activates expression of the human tumour-suppressor protein p14ARF (the mouse homologue is called p19ARF), which binds to the MDM2-p53 complex and prevents p53 degradation2,5.
How is ARF activated?
Because the ARF and DNA damage pathways that impinge on p53 are distinct, activation of ARF by low levels of Myc or E1A can sensitize cells to the p53-dependent effects of genotoxic drugs or irradiation (17).
What is ARF in p53?
The Arf/p53 pathway protects cells against several types of damage and this is the basis of its tumor suppressor activity. Interestingly, aging is a process associated with the accumulation of damage derived from chronic stresses of small magnitude.
How does p14ARF regulate p53?
p14ARF inhibits Mdm2-dependent p53 degradation, through Mdm2-p14ARF complex formation (Zhang et al., 1998). Thus, in response to genotoxic stress induced by gamma-radiation, p14ARF binds directly to Mdm2, leading to an inhibition of Mdm2-mediated p53 ubiquitination and degradation, which increases p53 levels.
How does MDM2 regulate p53?
MDM2 negatively regulates p53 by targeting the ubiquitin ligase activity of MDM2. A complementary approach to prevent p53 degradation by MDM2 is to develop agents designed to inhibit the E3 ligase activity of MDM2 directly so as to mimic the effects of ARF or the ribosomal protein L11.
What does ARF do to MDM2?
We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1β–encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation.
What cancers are associated with p21?
In 1994, p21 (also known as wildtype activating factor-1/cyclin-dependent kinase inhibitory protein-1 or WAF1/CIP1) was introduced as a tumor suppressor in brain, lung, and colon cancer cells; it was shown that p21 induces tumor growth suppression through wild type p53 activity [2].
What is an alternate reading frame?
Introduction. The p14 Alternate Reading Frame (ARF) protein is a cancer-associated protein that plays a well-characterized role in activating the p53 tumor suppressor pathway. ARF is present in normal cells at low to undetectable levels but accumulates in response to oncogene activation [1]–[6].
What is the function of p14ARF?
What is ARF gap?
Arf GAPs (ADP-ribosylation factor GTPase activating proteins) are essential components of Arf (ADP-ribosylation factor) signaling pathways. Arf GAPs stimulate the hydrolysis of GTP to GDP to transition Arf from the active, GTP bound, state to the inactive, GDP bound, state.
What is p14ARF in cancer?
p14ARF (also called ARF tumor suppressor, ARF, p14ARF) is an a lternate r eading f rame protein product of the CDKN2A locus (i.e. INK4a/ARF locus). p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein).
How do tumor suppressors p16 INK4a and p14 ARF work?
It encodes tumor suppressors p16 INK4a, and also p14 ARF, which acts via the p53 pathway to induce cell cycle arrest or apoptosis [25,26]. The tumor suppressor protein 16 INK4a binds to the cyclin-D-dependent protein kinases Cdk4 and 6, blocking their activity and preventing retinoblastoma protein (Rb) phosphorylation.
What is the role of p14ARF in p53 activation?
p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle.
How does p14ARF inhibit Mdm2 function?
p14ARF inhibits MDM2 function preventing degradation of p53 [37,38]. Leilei Fu, Bo Liu, in Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, 2016