Retinoblastoma-binding protein 2-homolog 1: a retinoblastoma-binding protein downregulated in malignant melanomas.
In malignant melanomas, the loss of cell cycle control is thought to be due to a lack of retinoblastoma protein (pRb)-activity. Members of the previously described family of retinoblastoma-binding proteins (RBPs) are supposed to act as pRb-modulating factors. Based on RNA-fingerprinting of normal human melanocytes, we previously described a new family member with high sequence homology to the retinoblastoma-binding protein-2 (RBP-2), termed RBP2-Homolog 1 (RBP2-H1). Based on its UVB responsiveness, it was hypothesized that this gene may also play a role in melanocytic tumors. In the present study, we can confirm by real-time RT-PCR (six common melanocytic nevi, five advanced nodular melanomas and seven melanoma metastases) and immunohistochemistry (tissue microarrays: 52 melanocytic nevi, 60 melanomas, 60 metastases; and conventional sections: five common nevi, four advanced nodular melanomas, five melanoma metastases) that RBP2-H1 expression is progressively downregulated in advanced and metastatic melanomas in vivo with a certain intratumoral heterogeneity. Whereas benign melanocytic nevi are RBP2-H1 positive in about 70% of the cases, a lack of RBP2-H1 expression was found in 90% of the primary malignant melanomas and 70% of the melanoma metastases, respectively. Interestingly, a similar deficiency can be found in glioblastomas, but not epithelial cancers. In accordance to the in vivo data, established melanoma cell lines exhibit low but heterogeneous levels of RBP2-H1 expression. By co-immunoprecipitation, we provide the first evidence that a subfraction of total RBP2-H1 can bind to pRb, which makes this protein a true pRb-interacting factor. We conclude that loss of RBP2-H1 is a common finding in the progression of malignant melanomas. Since a direct interaction of RBP2-H1 and pRb seems possible, the loss of RBP2-H1 may possibly contribute to uncontrolled growth in malignant melanomas.
Roesch
Alexander
A
Department of Dermatology, University of Regensburg, Regensburg, Germany. alexander.roesch@klinik.uni-regensburg.de
Becker
Bernd
B
Meyer
Stefanie
S
Wild
Peter
P
Hafner
Christian
C
Landthaler
Michael
M
Vogt
Thomas
T
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008545:Melanoma / Q000378:metabolism*; D008969:Molecular Sequence Data; D009506:Nevus / Q000378:metabolism; D010802:Phylogeny; D012333:RNA, Messenger / Q000032:analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000378:metabolism*; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2