Regenerating proteins and their expression, regulation, and signaling

Abstract

The regenerating (Reg) protein family comprises C-type lectin-like proteins discovered independently during pancreatitis and pancreatic islet regeneration. However, an increasing number of studies provide evidence of participation of Reg proteins in the proliferation and differentiation of diverse cell types. Moreover, Reg family members are associated with various pathologies, including diabetes and forms of gastrointestinal cancer. These findings have led to the emergence of key roles for Reg proteins as anti-inflammatory, antiapoptotic and mitogenic agents in multiple physiologic and disease contexts. Yet, there are significant gaps in our knowledge regarding the regulation of expression of different Reg genes. In addition, the pathways relaying Reg-triggered signals, their targets and potential cross-talk with other cascades are still largely unknown. In this review, the expression patterns of different Reg members in the pancreas and extrapancreatic tissues are described. Moreover, factors known to modulate Reg levels in different cell types are discussed. Several signaling pathways, which have been implicated in conferring the effects of Reg ligands to date, are also delineated. Further efforts are necessary for elucidating the biological processes underlying the action of Reg proteins and their involvement in various maladies. Better understanding of the function of Reg genes and proteins will be beneficial in the design and development of therapies utilizing or targeting this protein group.

The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis

“…We confirmed decreased expression of the Ang4 bactericidal peptide gene, expressed in Paneth and goblet cells (5, 28) (Fig. 1B), as well as increased expression of antimicrobial C-type lectin genes Reg3␤ and Reg3␥ (45), expressed in enterocytes and in Paneth and goblet cells (5) (Fig. 1C).…”

“…Thus novel homeostatic anti-inflammatory signals may be induced. One of the anti-inflammatory proteins induced is Reg3g, an antibacterial C-type lectin (45) that segregates the microbiota from the mucosal intestinal surface (62) and displays bactericidal activities selective for gram-positive bacteria (7). Reg3g is induced in IBD (44,63).…”

Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

“…The Reg proteins are small secreted proteins belonging to the calcium-dependent lectin (C-type lectin) superfamily, encoded by four genes (Reg1, -2, -3, and -4). Reg1 is predominantly localized to acinar cells; however, it may be upregulated in islets under pathological conditions, including pancreatic resection or diabetes (36). Although it is unclear how Ex-4 induces Reg gene and protein expression, Reg expression is induced by proinflammatory cytokines, growth factors, and experimental pancreatic injury (36).…”

“…Reg1 is predominantly localized to acinar cells; however, it may be upregulated in islets under pathological conditions, including pancreatic resection or diabetes (36). Although it is unclear how Ex-4 induces Reg gene and protein expression, Reg expression is induced by proinflammatory cytokines, growth factors, and experimental pancreatic injury (36). Some investigators have inferred that induction of pancreatic Reg3 expression reflects the presence of mild subclinical pancreatitis (37); however, Reg proteins, including Reg3, also exert anti-inflammatory actions (38), and reduction of Reg expression significantly worsened the severity of experimental pancreatitis in rats (39).…”

Serum regenerating islet‐derived 3‐alpha is a biomarker of mucosal enteropathies

“…[7][8][9] In humans, the Reg gene family currently consists in four well-established members (Reg1a, Reg1b, Reg3a and Reg4), which are found encoded in tandem on chromosome 2p12, except for Reg4, which is found on 1p12. 10 All Regs are produced in the pancreas and small intestine, whereas Reg4 is only constitutively expressed in colonic epithelium, 11 and their expression is enhanced during inflammatory processes. For example, high Reg1a is seen in inflamed intestinal epithelium of patients with inflammatory bowel disease (IBD) and patients with non-IBD colitis 12,13 as well as in the circulation of patients with active CD (ACD).…”