Regular Article
Cloning and Characterization of Novel CIS Family Genes

https://doi.org/10.1006/bbrc.1997.7484Get rights and content

Abstract

We have reported two JAK-signaling modulators, CIS (cytokine-inducible SH2 protein) and JAB (JAK2 binding protein), which are structurally related. Here we cloned three additional CIS family genes (CIS2, CIS3, and CIS4) on the basis of an expression sequence tag (EST) database search. We also found at least two additional candidates of this gene family in the database. These genes were induced by erythropoietin and granulocyte-macrophage colony stimulating factor in certain hematopoietic cell lines. The SH2 domain and a C-terminal 40 amino acid region, designated the CIS homology domain (CH domain), are highly conserved in this family, while the N-terminal regions of these proteins share little similarity. A yeast two-hybrid assay andin vitroandin vivobinding assays revealed that in addition to JAB, CIS3 bound to the JAK2 tyrosine kinase domain (JH1), although the interaction of CIS3 with the JAK2-JH1 domain was much weaker than that of JAB. Transient expression of JAB and CIS3, but not other CISs, strongly inhibited leukemia inhibitory factor (LIF)-induced STAT3-reporter gene activation in 293 cells. Furthermore, constitutive overexpression of JAB and CIS3 in M1 leukemia cells prevented LIF-induced differentiation and growth arrest. Although the physiological function remains to be investigated, CIS family genes could play a role in the negative regulation of cytokine signaling by interacting with specific targets.

References (24)

  • J.N. Ihle

    Cell

    (1996)
  • T. Tauchi et al.

    Blood

    (1996)
  • U. Klingmuller et al.

    Cell

    (1995)
  • A. Matsumoto et al.

    Blood

    (1997)
  • S. Chiba et al.

    Blood

    (1991)
  • H. Kitayama et al.

    Blood

    (1995)
  • K. Arai et al.

    Annu. Rev. Biochem.

    (1990)
  • J.N. Ihle

    Nature

    (1995)
  • J.E.J. Darnell et al.

    Science

    (1994)
  • T.K. Sengupta et al.

    Proc. Natl. Acad. Sci. USA.

    (1996)
  • T.K. Kim et al.

    Science

    (1996)
  • Cited by (216)

    View all citing articles on Scopus
    1

    Corresponding author. Fax: 81-942-31-5212. E-mail: [email protected].

    View full text