Review
MafA and MafB activity in pancreatic β cells

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Analyses in mouse models have revealed crucial roles for MafA (musculoaponeurotic fibrosarcoma oncogene family A) and MafB in islet β cells, with MafB being required during development and MafA in adults. These two closely related transcription factors regulate many genes essential for glucose sensing and insulin secretion in a cooperative and sequential manner. Significantly, the switch from MafB to MafA expression also appears to be vital for functional maturation of β cells produced by human embryonic stem (hES) cell differentiation. This review summarizes the discovery, distribution, and function of MafA and MafB in rodent pancreatic β cells, and describes some key questions regarding their importance to β cells.

Section snippets

β Cell generation as a source of replacement therapy for diabetes mellitus

Pancreatic islet β cells are the only cell type in the body to secrete the hormone insulin in response to glucose. High levels of glucose stimulate insulin secretion from β cells. This hormone first acts on liver to increase glycogen synthesis and inhibit gluconeogenesis. Subsequently, insulin promotes glucose uptake and storage in skeletal muscle and adipose tissue. In addition to increased blood glucose concentrations, insulin is also secreted in response to amino acids, free fatty acids,

MafA and MafB are the principal large Maf transcription factors in the pancreas

The family of large Maf proteins is composed of four distinct genes/proteins (Box 1), MafA, MafB, c-Maf and Nrl, which all contain N-terminal transactivation and C-terminal basic leucine-zipper DNA-binding domains. The in vitro DNA-binding properties of MafA, MafB, and c-Maf are indistinguishable [23]. c-Maf has been reported to be expressed in the pancreas 20, 24, 25, 26, whereas pancreatic Nrl expression is undetectable [27]. Significantly, pancreas development is unaffected in c-Maf null

MafA and MafB have unusual expression patterns during islet cell development

MafA and MafB are expressed in a unique temporospatially regulated manner in relation to other islet-enriched factors in developing and postnatal murine islet cells. MafB is expressed earlier than MafA, with initial production being detected around embryonic (E) day E10.5 in the pancreatic epithelium 20, 25. By contrast, MafA is first produced at E13.5 and only in insulin+ cells [43]. Their developmental expression patterns are also unusually late in comparison to all other islet-enriched

Only MafB is required during mouse β cell development.

The pancreatic transcription factors play important roles in pancreas development (Figure 2). Almost all these transcription factor knockout mice result in either the loss in hormone+ cell numbers and/or respecification to another islet cell type 47, 48, 49, 52. For instance, Pdx1 is crucial for pancreas outgrowth during development, with loss leading to pancreas agenesis in mice and humans 52, 53, 54. This condition results in death soon after birth unless treated for the loss of

The potential role of MafA and MafB in islet β cell generation from non-β cells

In view of the significance of MafA in glucose-responsive transcription and adult β function, MafA has been used to induce β cell differentiation in both human and rodent stem cells and differentiated cell types (Table 1). The MafA protein, alone or in combination with other pancreatic transcription factors, was able to induce the expression of insulin and other key β cell markers. In most cases the generated insulin+ cells improved blood glucose levels in streptozotocin-induced diabetic

Concluding remarks

Studies on MafA and MafB using mouse models have revealed their crucial roles in islet β cell formation and function, with MafB being required during development and MafA in adults. Gene-expression analyses disclosed that the two closely related transcription factors regulate key β cell genes in a cooperative and sequential manner. Research both in mouse models and in hES cell differentiation in vitro showed that the switch from MafB+ to MafA+ is vital for functional maturation of β cells.

Acknowledgments

R.S. is supported by grants from the National Institutes of Health (DK050203, DK077971, and DK089572).

References (120)

  • R. Ashery-Padan

    Conditional inactivation of Pax6 in the pancreas causes early onset of diabetes

    Dev. Biol.

    (2004)
  • M. Gannon

    Pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis

    Dev. Biol.

    (2008)
  • K. Kataoka

    MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene

    J. Biol. Chem.

    (2002)
  • S.Y. Shieh et al.

    Cell-specific and ubiquitous factors are responsible for the enhancer activity of the rat insulin II gene

    J. Biol. Chem.

    (1991)
  • N.L. Vanderford

    Glucose induces MafA expression in pancreatic beta cell lines via the hexosamine biosynthetic pathway

    J. Biol. Chem.

    (2007)
  • N. Rocques

    GSK-3-mediated phosphorylation enhances Maf-transforming activity

    Mol. Cell

    (2007)
  • S. Guo

    The stability and transactivation potential of the mammalian MafA transcription factor are regulated by serine 65 phosphorylation

    J. Biol. Chem.

    (2009)
  • L. Zhao

    The RIPE3b1 activator of the insulin gene is composed of a protein(s) of approximately 43 kDa, whose DNA binding activity is inhibited by protein phosphatase treatment

    J. Biol. Chem.

    (2000)
  • S. Guo

    Phosphorylation within the MafA N terminus regulates C-terminal dimerization and DNA binding

    J. Biol. Chem.

    (2010)
  • J.S. Harmon

    Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells

    J. Biol. Chem.

    (2005)
  • Y.I. Kitamura

    FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction

    Cell Metab.

    (2005)
  • D.K. Hagman

    Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans

    J. Biol. Chem.

    (2005)
  • S. Lenzen

    Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues

    Free Radic. Biol. Med.

    (1996)
  • V. Blank et al.

    The Maf transcription factors: regulators of differentiation

    Trends Biochem. Sci.

    (1997)
  • H. Motohashi

    Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors

    Gene

    (2002)
  • A.M. Shapiro

    Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen

    N. Engl. J. Med.

    (2000)
  • A.M. Ackermann et al.

    Molecular regulation of pancreatic beta-cell mass development, maintenance, and expansion

    J. Mol. Endocrinol.

    (2007)
  • D.T. Finegood

    Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model

    Diabetes

    (1995)
  • M. Teta

    Very slow turnover of beta-cells in aged adult mice

    Diabetes

    (2005)
  • L.C. Alonso

    Glucose infusion in mice: a new model to induce beta-cell replication

    Diabetes

    (2007)
  • P.J. Miettinen

    Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal beta-cell growth

    Diabetes

    (2006)
  • Y. Dor

    Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation

    Nature

    (2004)
  • S.N. Flier

    Evidence for a circulating islet cell growth factor in insulin-resistant states

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • A.E. Butler

    Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

    Diabetes

    (2003)
  • B.A. Menge

    Partial pancreatectomy in adult humans does not provoke beta-cell regeneration

    Diabetes

    (2008)
  • S. Georgia et al.

    Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass

    J. Clin. Invest.

    (2004)
  • J.A. Kushner

    Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth

    Mol. Cell. Biol.

    (2005)
  • N. Fiaschi-Taesch

    Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo

    Diabetes

    (2009)
  • J.A. Lavine

    Contamination with E1A-positive wild-type adenovirus accounts for species-specific stimulation of islet cell proliferation by CCK: a cautionary note

    Mol. Endocrinol.

    (2010)
  • N.M. Fiaschi-Taesch

    Induction of human beta-cell proliferation and engraftment using a single G1/S regulatory molecule, cdk6

    Diabetes

    (2010)
  • K.A. D’Amour

    Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells

    Nat. Biotechnol.

    (2006)
  • E. Kroon

    Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo

    Nat. Biotechnol.

    (2008)
  • I. Artner

    MafB is required for islet beta cell maturation

    Proc. Natl. Acad. Sci. U.S.A.

    (2007)
  • I. Artner

    MafA and MafB regulate genes critical to β cells in a unique temporal manner

    Diabetes

    (2010)
  • Q. Zhou

    In vivo reprogramming of adult pancreatic exocrine cells to beta-cells

    Nature

    (2008)
  • H. Wang

    MAFA controls genes implicated in insulin biosynthesis and secretion

    Diabetologia

    (2007)
  • T.A. Matsuoka

    Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells

    Mol. Cell. Biol.

    (2003)
  • K. Kataoka

    Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells

    J. Mol. Endocrinol.

    (2004)
  • I. Artner

    MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells

    Diabetes

    (2006)
  • Q. Liu

    Expression of the bZIP transcription factor gene Nrl in the developing nervous system

    Oncogene

    (1996)
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