Abstract
Following the event of DNA damage, the level of tumour suppressor protein p53 increases inducing either cell cycle arrest or apoptosis. Junctional Mediating and Regulating Y protein (JMY) is a transcription co-factor involved in p53 regulation. In event of DNA damage, JMY levels also upregulate in the nucleus where JMY forms a co-activator complex with p300/CREB-binding protein (p300/CBP), Apoptosis-stimulating protein of p53 (ASPP) and Stress responsive activator of p53 (Strap). This co-activator complex then binds to and increases the ability of p53 to induce transcription of proteins triggering apoptosis but not cell cycle arrest. This then suggests that the increase of JMY levels due to DNA damage putatively “directs” p53 activity toward triggering apoptosis. JMY expression is also linked to increased cell motility as it: (1) downregulates the expression of adhesion molecules of the Cadherin family and (2) induces actin nucleation, making cells less adhesive and more mobile, favouring metastasis. All these characteristics taken together imply that JMY possesses both tumour suppressive and tumour metastasis promoting capabilities.
Highlights
A salient observation in cancer biology has been that TP53 is frequently mutated in many human tumours [1,2]. p53 protein was identified in SV40 transformed cells where it was associated with Large T Antigen
It is highly speculated that p53 selectively activates transcription of pro-apoptotic target genes upon interaction with transcriptional co-activators such as p300/CREB-binding protein (p300/CBP), Junctional and regulatory protein (JMY), Stress responsive activator of p53 (Strap) and Apoptosis-stimulating protein of p53 (ASPP) [2,5]
DNA damage is one of the triggers for activation of factors that regulate Junctional Mediating and Regulating Y protein (JMY) such as: (1) E2F1 which mediates increased expression of JMY; (2) Strap and p300 which form a co-activator complex with JMY switching on p53 induced apoptosis; and (3) Mouse Double Minute 2 homolog (MDM2) which releases bound JMY to participate in p53 induced apoptosis response
Summary
A salient observation in cancer biology has been that TP53 is frequently mutated in many human tumours [1,2]. p53 protein was identified in SV40 transformed cells where it was associated with Large T Antigen. Interesting, Coutts et al have demonstrated that JMY localizes in the nucleus and cytoplasm but following stress or DNA damage, JMY migrates from the cytoplasm to the nucleus to transcriptionally enhance P53’s response [11] According to this group, when JMY shuttles into the nucleus, JMY’s contribution to cell motility diminishes [11]. This implies that JMY is playing a dichotomous role in cancer biology: (1) having a tumour suppressive capacity in the event of DNA damage where it enhances p53 activity and (2) functioning as a putative tumour metastasis promoter due to its ability to downregulate E-cadherin, nucleate actin filament and contribute to cell motility. It is important to reconcile the role and cue of JMY in these two different cellular processes of programmed cell death versus actin dynamics regulation of tumourigenesis
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