Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1998-03-13
2002-08-13
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S012200, C514S021800
Reexamination Certificate
active
06432410
ABSTRACT:
INTRODUCTION
1. Field of the Invention
The field of this invention is proteins which regulate cell function, and in particular, antagonize bone morphogenic proteins.
2. Background
Natural regulators of cellular growth, differentiation and function have provided important pharmaceuticals, clinical and laboratory tools, and targets for therapeutic intervention. A variety of such regulators have been shown to have profound effects on basic cellular differentiation and developmental pathways. For example, the recently cloned cerberus protein induces the formation of head structures in anterior endoderm of vertebrate embryos. Similarly, the noggin protein induces head structures in vertebrate embryos, and can redirect mesodermal fates from ventral fates, such as blood and mesenchyme, to dorsal fates such as muscle and notochord and can redirect epidermal fates to anterior neural fates. The activities of chordin are similar to those of noggin, reflecting a common mechanism of action; namely antagonizing bone morphogenic proteins (BMP) and thereby preventing their function. BMPs have diverse biological activities in different biological contexts, including the induction of cartilage and bone, connective tissue, and roles in kidney, tooth, gut skin and hair development.
Different members of the TGF&bgr; superfamily can instruct cells to follow different fates, for example TGF&bgr; induces neural crest to form smooth muscle, while BMP2 induces the same cells to become neurons. In Xenopus experiments, dissociated animal cap cells (prospective ectoderm) become epidermis in response to BMP4 but become mesoderm in response to activin. Since the identity between activin and BMP4 is low, it is not surprising that they induce different fates. It is more surprising that members of the BMP subfamily, which are quite closely related in sequence, can induce distinct fates. A striking example results from implantation of a matrix impregnated with a BMP into muscle; when the effects are monitored histologically, BMP2, 4 and 7 induce endochondral bone formation, whereas a related molecule BMP 12/GDF7 induces connective tissue similar to tendon. Similarly, BMP4 can induce cell death in the hindbrain neural crest, while the related protein dorsalin does not.
Since different BMP family members can induce different fates, then BMP antagonists that have specificity in blocking subsets of BMPs could change the balance of BMPs that are presented to a cell, thus altering cell fate. In view of the importance of relative BMP expression in human health and disease, regulators of cellular function and BMP function in particular; such as noggin and cerberus, provide valuable reagents with a host of clinical and biotechndlogical applications.
The present invention relates to a new family of regulators of cellular function; in particular, we have identified a new dorsalizing factor Gremlin. Gremlin's activities are similar to those of Noggin and Chordin, however, it has no sequence similarity to them, and it is not expressed during gastrulation. Instead, zygotic Gremlin expression begins in the migrating neural crest, highlighting a potential role for organizer-like activities in the development of this cell lineage. Furthermore, we have identified a structurally and functionally-related family of proteins that includes Gremlin, the head-inducing factor Cerberus and the tumor suppressor DAN (Ozaki and Sakiyama, 1993; Bouwmeester et al., 1996). We have named this family the DAN family for the first member identified. Cerberus is expressed in the anterior endomesoderm of the gastrula organizer and has been proposed to participate in head induction (Bouwmeester et al., 1996). DAN was isolated as a putative zinc-finger protein 4downregulated in transformed cells and was subsequently shown to have tumor suppressor activity (Ozaki and Sakiyama, 1993; Ozaki and Sakiyama, 1994). Similarly, the rat homolog of Gremlin, drm, has also been proposed to have a role in controlling cell growth and differentiation (Topol et al., 1997). We demonstrate that all members of the DAN family act as BMP antagonists, while Cerberus alone blocks the activity of Activin and Nodal-like activities. We also show that DAN-family members are secreted proteins that bind BMP-2. Together, our data reveal that individual DAN-family members block the activity of specific TGF-&bgr; ligands by binding them and preventing them from interacting with their cell surface receptors.
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SUMMARY OF THE INVENTION
The invention provides methods and compositions relating to DAN (Differential-screening-selected gene Aberrative in Neuroblastoma) and gremlin proteins and related nucleic ac
Harland Richard
Hsu David
Kunz Gary L.
Osman Richard Aron
The Regents of the University of California
Turner Sharon
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