Connexin 43
(Cx43)

Gap junction protein, alpha-1 (GJA1)
Gap junction protein, 43 kD
Heart connexin

Gene: GJA1 maps to 6q21-q23.2 (Corcos I.A. et al., 1993).
mRNA: size: kb
Protein:

Alteration of gap junctional intercellular communication (GJIC) is among the early changes associated with carcinogenesis and restoration of gap junctions can suppress tumor cell growth.
GJIC mediates the transfer of ions, nucleotides, and small regulatory molecules from cytoplasm to cytoplasm without leakage into the extracellular space.
Gap junctions are composed of multiple hemichannels (connexons) in the plasma membrane of one cell joined in mirror symmetry with the same number of hemichannels in the apposing cell membrane. Connexons are formed by members of a multigene family of distinct but functionnally related proteins called connexins (Cxs).
Gap junctions are dynamic structures with relatively short half-lives of 1-5 h. They are tightly regulated by voltage, growth factors, a number of secondary messengers including cAMP and retinoids and are subjected to phosphorylation by a number of protein kinases.
While at least 15 Cxs genes have been identified in mammalian cells, expression of three of them (Cx43, Cx26, Cx32) has been detected in normal breast tissue. Cx43 is the predominant Cx in human breast epithelium, and it was detected predominantly between myo-epithelial cells (Monaghan P. et al., 1996). There is evidence suggesting that Cxs may play a role in normal mammmogenesis, lactogenesis, and involution. It has been shown that Cx26 levels in the epithelium increase substantially in the lactating mouse mammary gland epithelium and decline during involution, and hormones such as estrogens and progesterones have been shown to regulate the expression of the Cx43 gene.

Cell lines:
- Both Cx26 and Cx43 suppressed the cancer phenotype of MDA-MB-435 breast cancer cells (BCC) and suppressed cell growth in culture and in animal models (Hirschi K.K. et al., 1996).

- Cx43 protein and mRNA were found in MDA-MB-231 and Hs578T BCC lines, but not in ZR-75, MDA-MB-468, and T-47D BCC lines (Laird D.W. et al., 1999).

Tumors:
- In a series of 32 breast tumor specimens obtained from patients who underwent a primary surgical resection prior to chemotherapy or radiotherapy treatments, the lack of Cx43 gap junctions was found to be a common feature of cancer tissues compared to nonneoplastic breast tissues surrounding primary tumors. Cx43 gap junctions were not observed in ductal carcinomas in situ, infiltrating ductal carcinomas, and infiltrating lobular carcinomas, and they seem to be independent of estrogen receptor, progesterone receptor, and erbB2 status (Laird D.W. et al., 1999).

Corcos I.A. et al. (1993) Human connexin 43 gene locus, GJA1, sublocalized to band 6q21-q23.2. Cytogenet. Cell Genet. 64, 31-32.
Fishman G.I. et al. (1990) Molecular characterization and functional expression of the human cardiac gap junction channel. J. Cell. Biol. 111, 589-598.
Hirschi K.K. et al. (1996) Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. Cell. Growth Differ. 7, 861-870.
Jamieson S. et al. (1998) Expression of gap junction proteins connexin26 and connexin43 in normal human breast and in breast tumors. J. Pathol. 184, 37-43.
Laird D.W. et al. (1999) Deficiency of connexin43 gap junctions is an independent marker for breast tumors. Cancer Res. 59, 4104-4110.
Monaghan P. et al. (1996) Gap junction distribution and connexin expression in human breast. Exp. Cell. Res. 223, 29-38.
Wilgenbus K.K. et al. (1992) Expression of Cx26, Cx32 and Cx43 gap junction proteins in normal and neoplastic human tissues. Int. J. Cancer 51, 522-529.

Under construction