RETINOID SIGNALING IN HEALTH AND DISEASE

Harini Laxminarayan: ON DEMAND ORAL PRESENTATION AT ACS FALL 2020 VIRTUAL CONFERENCE--17/AUG/2020

HYPOTHESIS: Interaction of Vitamin A/ Retinoic acid with Human Kinome could reveal several areas that can be explored to develop anti-cancer drug targets.

A sub population of RAR alpha is present in membrane lipid rafts and initiates cascades of kinase activations upon RA binding. RA—-RAR alpha complex interacts with G proteins and activates Rho-GTPases, p38 MAPK and MSK1.(Al Tanoury, Piskunov and Rochette-Egly, 2013) Epithelial and Fibroblast cells: RA—-RAR alpha complex interacts with G proteins and activates Rho-GTPases, p38 MAPK and MSK1. Neuronal cells: RA—-RAR alpha complex activates Erks through the activation of PI3K/Akt pathway and Src kinase.

Vita A bound to RBP triggers the phosphorylation of the cytoplasmic domain of STRA6 in the lipid raft. Phosphorylated STRA6 recruits and activates JAK2, which intern phosphorylates STAT5. STAT5 translocates to the nucleus to regulate gene expression. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, differentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. (Tsygankov, 2003)

Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis. ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer. Specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway.(Sun et al., 2015) Effects of vitamin D3 on extracellular signal-related kinase (ERK). 1,25-(OH)2 D3 , a form active in inducing transcription, caused rapid and transient ERK activation. (INOUE, ISHIMI and YAMAUCHI, 2008) Consequently, one can speculate that the integrity of all these pathways would be required for “correct” RA and vitamin A signalling. This case in point is seen in in xeroderma pigmentosum patients, who are characterised by mutations affecting subunits of the core of the general transcription factor TFIIH. Here, RAR︎ is not efficiently phosphorylated by cdk7, with characteristic downtream consequences on the expression of RAR target gene. Deregulation of the “kinome” has deleterious downstream effects. (Keriel et al., 2002) In line with this hypothesis, our project aims to study the effects of RA on cytosolic kinase cascades involving Akt, MAPKs (Erk, JNK, p38MAPK). In cancers, RA induced activation of MAPK pathway is abrogated, and RAR/RXR(alpha) are aberrantly phosphorylated. It is believed that the results will provide additional insights into the molecular mechanism operating in cancers, uncover possible drug targets for anti-cancer therapies and emphasise the role of nutrition in drafting national and global food based dietary guidelines. (512 words)